TMEM43 (Transmembrane Protein 43 / Protein LUMA): A Comprehensive Functional Analysis

Introduction and Summary

TMEM43 (Transmembrane Protein 43), also known as protein LUMA, is a highly conserved integral membrane protein that has emerged as a multifunctional molecule with critical roles in cardiac, auditory, and muscular physiology. Originally identified as a protein of unknown function, TMEM43 gained clinical prominence in 2008 when Merner and colleagues identified the p.S358L missense mutation as the causative variant for arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) in a founder population from Newfoundland, Canada[merner-2008-ARVC5-abstract]. Since then, research has revealed that TMEM43 functions at multiple subcellular locations and participates in diverse cellular processes including mechanotransduction, gap junction communication, and ion channel function.

The human TMEM43 gene encodes a 400 amino acid protein belonging to the TMEM43 family (InterPro: IPR012430, Pfam: PF07787). According to PubMed, the protein contains four predicted transmembrane domains with one intramembrane domain, and both N- and C-termini oriented extracellularly[kang-2024-TMEM-ion-channels-summary]. Recent evidence has established that TMEM43 functions as a nonselective cation channel, earning it the alternative designation "Gapjinc" (Gap junction interacting channel) due to its intimate association with connexin gap junction proteins[kang-2024-TMEM-ion-channels-summary]. The protein localizes to multiple cellular compartments including the inner nuclear membrane, endoplasmic reticulum, and plasma membrane, as well as cardiac intercalated discs and epithelial adherens junctions[orgil-2025-TMEM43-review-abstract][franke-2014-intercalated-disc-abstract].

Molecular Structure and Topology

TMEM43 is predicted to contain four transmembrane (TM) domains based on hydrophobicity analysis, with the secondary structure featuring four TMs and one intramembrane domain. Both N-terminal and C-terminal domains are oriented toward the extracellular/luminal space[jang-2021-ANSD-summary]. This topology has been experimentally verified through immunocytochemistry with and without cell permeabilization, demonstrating that the intracellular loop 1 region (residues 203-308) resides in the cytoplasm[jang-2021-ANSD-summary].

A high-resolution three-dimensional structure of TMEM43 has not yet been determined experimentally through crystallography or cryo-electron microscopy. AlphaFold2 predictions of the monomeric architecture reveal a somewhat scrambled intramembrane domain configuration, suggesting that the protein may require additional structural context for proper folding[kang-2024-TMEM-ion-channels-summary]. The protein is phylogenetically conserved across species, with the transmembrane domains showing particularly high conservation from invertebrates to humans[jang-2021-ANSD-summary]. Notably, the serine at position 358, whose mutation to leucine causes ARVC5, lies within a highly conserved transmembrane domain[merner-2008-ARVC5-abstract].

TMEM43 forms oligomeric complexes that are essential for its function. Studies by Liang and colleagues demonstrated that the p.E85K mutation in the EDMD-related myopathy causes failure of LUMA oligomerization, a process critical for protein complex formation at the nuclear membrane[liang-2011-EDMD-abstract]. The ability to oligomerize appears to be important for TMEM43's interaction with its various binding partners including emerin, lamins, SUN2, and connexins.

Subcellular Localization

The subcellular localization of TMEM43 has been a subject of significant investigation and some controversy. Early studies established TMEM43 as an inner nuclear membrane protein, associated with the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. The LINC complex provides mechanical coupling between the nuclear envelope and the cytoskeleton, playing critical roles in mechanotransduction, nuclear positioning, and chromatin organization[meinke-2011-LINC-complex-abstract][stroud-2018-mouse-knockout-abstract].

However, subsequent immunolocalization studies by Franke and colleagues challenged the exclusive nuclear envelope localization model. Using highly specific antibodies, they discovered that in mammalian tissues, LUMA is a component of zonula adhaerens and punctum adhaerens plaques in diverse epithelia, and is also located in composite junctions (CJs) at myocardial intercalated disks[franke-2014-intercalated-disc-abstract]. Importantly, in these cell types, LUMA was not detected in the nuclear envelope, suggesting tissue-specific or condition-specific localization patterns.

In the cochlea, TMEM43 shows a distinct expression pattern primarily in glia-like supporting cells (GLSs) rather than hair cells. At postnatal day 4 through P20, TMEM43 is mainly expressed in the organ of Corti, becoming more restricted to the apical membrane of inner border cells and cell junctions of inner sulcus cells by P20[jang-2021-ANSD-summary]. Expression persists in adult mice at 1, 2, and 4 months of age, and similar GLS-specific expression has been confirmed in adult primates corresponding to humans in their 40s[jang-2021-ANSD-summary].

In cardiac tissue, mouse studies revealed that Luma is sporadically expressed in cardiomyocytes throughout the heart but is highly and uniformly expressed in cardiac fibroblasts and vascular smooth muscle cells[stroud-2018-mouse-knockout-abstract]. This expression pattern suggests that TMEM43's primary cardiac function may involve non-cardiomyocyte cell populations or intercellular communication rather than intrinsic cardiomyocyte biology.

Primary Molecular Function: Ion Channel Activity

Based on PubMed, recent electrophysiological studies have established TMEM43 as a bona fide ion channel with nonselective cation permeability. The channel is permeable to Na+, K+, and Cs+ ions and mediates passive conductance-like currents when expressed heterologously[kang-2024-TMEM-ion-channels-summary]. Several lines of evidence support its identity as a pore-forming channel: purified TMEM43 protein reconstituted into lipid bilayers displays stochastic single-channel openings, and gene silencing of TMEM43 eliminates carbenoxolone (CBX)-, gadolinium (Gd3+)-, and low pH-sensitive passive conductance currents in cochlear GLSs[kang-2024-TMEM-ion-channels-summary].

The channel displays sensitivity to extracellular pH, with current amplitude decreasing progressively as pH is lowered from 8 to 5.5[kang-2024-TMEM-ion-channels-summary]. This pH sensitivity is physiologically significant, as lowering the extracellular pH to 6 completely abolishes the passive conductance current in GLSs[jang-2021-ANSD-summary]. The channel is blocked by the nonselective cation channel inhibitor gadolinium chloride (GdCl3) and by carbenoxolone, a gap junction blocker[jang-2021-ANSD-summary].

A crucial aspect of TMEM43's ion channel function is its interaction with gap junction proteins. In the cochlea, TMEM43 interacts physically with Connexin26 (Cx26/GJB2) and Connexin30 (Cx30/GJB6), the two predominant connexins expressed in cochlear GLSs[jang-2021-ANSD-summary]. Co-immunoprecipitation assays demonstrated that both wild-type TMEM43 and the p.R372X mutant can be pulled down with either Cx26 or Cx30 when co-expressed in HEK293T cells. Duolink proximity ligation assays further confirmed close proximity (<40 nm) of TMEM43 and Cx26 in cochlear tissue[jang-2021-ANSD-summary].

TMEM43 also interacts with KCNK3 (TASK-1), a two-pore domain potassium (K2P) channel. The intracellular loop domain of TMEM43 is responsible for TASK-1 binding, suggesting a specific structural interface mediates this protein-protein interaction[jang-2021-TASK1-abstract]. Gene silencing of TMEM43 significantly reduces passive conductance current in GLSs, indicating that TMEM43 and its channel partners together mediate the background conductance essential for inner ear homeostasis[jang-2021-TASK1-abstract].

Role in the LINC Complex and Mechanotransduction

TMEM43/LUMA is associated with the LINC complex, which mechanically links the nucleoskeleton to the cytoskeleton via the nuclear envelope[stroud-2018-mouse-knockout-abstract][meinke-2011-LINC-complex-abstract]. The LINC complex components include emerin, lamin A/C, SUN1, SUN2, nesprin-1, and nesprin-2, all of which interact at the nuclear envelope with additional binding partners including actin filaments and B-type lamins[meinke-2011-LINC-complex-abstract].

TMEM43 was identified as a binding partner of emerin and lamins through protein interaction studies[meinke-2011-LINC-complex-abstract]. Furthermore, Liang and colleagues demonstrated for the first time that LUMA can interact with SUN2, another nuclear membrane protein, in addition to emerin[liang-2011-EDMD-abstract]. Cells expressing mutant LUMA showed reduced nuclear staining with or without aggregates of emerin and SUN2, together with a higher proportion of abnormally shaped nuclei, indicating that proper LUMA function is required for normal nuclear envelope organization[liang-2011-EDMD-abstract].

A key mechanistic insight into TMEM43's role in mechanotransduction comes from atomic force microscopy studies of patient-derived cells. Milting and colleagues demonstrated that skin fibroblasts from individuals carrying the TMEM43 p.S358L ARVC5 mutation exhibit increased nuclear stiffness compared to wild-type controls[milting-2014-european-founder-abstract]. This increased nuclear stiffness is hypothesized to contribute to the massive loss of cardiomyocytes characteristic of ARVC hearts, as stiffer nuclei may be more susceptible to damage under the mechanical strain experienced by beating cardiomyocytes[milting-2014-european-founder-abstract].

Role in Gap Junction Function and Intercellular Communication

In the cardiac context, the TMEM43 p.S358L mutation profoundly affects intercalated disc protein function. Siragam and colleagues demonstrated that stable expression of this mutation in HL-1 cardiac cells results in decreased expression of Zonula Occludens-1 (ZO-1) and loss of ZO-1 localization to cell-cell junctions[siragam-2014-ARVC-cell-abstract]. Junctional plakoglobin (JUP) and α-catenin proteins redistribute to the cytoplasm with decreased localization at cell-cell junctions. Critically, Connexin-43 (Cx43) phosphorylation is altered, gap junction dye transfer is reduced, and conduction velocity decreases in mutant TMEM43-transfected cells[siragam-2014-ARVC-cell-abstract]. These observations provide a direct mechanistic link between TMEM43 dysfunction and arrhythmogenesis through impaired gap junction communication.

In the cochlea, TMEM43's interaction with connexins is essential for maintaining the passive conductance current in GLSs. The passive current characteristics - sensitivity to CBX, Gd3+, and low pH - are consistent with gap junction-mediated ion flux, and gene silencing of TMEM43 dramatically reduces this current[jang-2021-ANSD-summary]. The p.R372X ANSD-causing mutation shows a dominant-negative effect, with heterozygous animals showing 63% reduction in passive conductance current compared to wild-type, while homozygous animals show 89% reduction[jang-2021-ANSD-summary].

Involvement in Wnt/β-Catenin Signaling and Adipogenesis

An important aspect of ARVC pathogenesis involves the Wnt/β-catenin signaling pathway. According to Lombardi and Marian, the pathogenesis of fibro-fatty replacement in ARVC involves partial nuclear translocation of plakoglobin and subsequent suppression of canonical Wnt signaling[lombardi-2011-wnt-signaling-abstract]. Since Wnt signaling is involved in the development of the right ventricle and its outflow tract (the predominant sites of ARVC involvement), suppression of this pathway results in a switch to adipogenesis in second heart field progenitor cells[lombardi-2011-wnt-signaling-abstract].

The TMEM43 gene contains a response element for PPARγ (peroxisome proliferator-activated receptor gamma), an adipogenic transcription factor[merner-2008-ARVC5-abstract]. This finding provides a potential molecular explanation for the fibro-fatty replacement of myocardium that is a characteristic pathological finding in ARVC. Recent work has shown that the TMEM43 p.S358L mutation is associated with increased absorption of lipids, fatty acids, and cholesterol in the mouse small intestine, which may further promote fibro-fatty replacement of cardiac myocytes[orgil-2025-TMEM43-review-abstract].

Role in Cancer Signaling: EGFR-NF-κB Pathway

Beyond its well-characterized roles in cardiac, auditory, and musculoskeletal function, TMEM43 has emerged as an important mediator of cancer signaling, particularly through the NF-κB pathway. Jiang and colleagues used a Bimolecular Fluorescence Complementation-based functional genomics method to perform high throughput screening and identified TMEM43/LUMA as a critical component in the EGFR signaling network[jiang-2017-cancer-NF-kB-abstract]. Their work revealed that following EGF stimulation, EGFR recruits TMEM43, which then interacts with the scaffold protein CARMA3 (CARD and MAGUK domain-containing protein 3) and its associated complex. This interaction induces downstream NF-κB activation and controls cell survival[jiang-2017-cancer-NF-kB-abstract].

TMEM43 deficiency profoundly affects cancer cell behavior, reducing colony formation, impairing survival of anoikis-induced cell death, and decreasing migration and invasion capabilities[jiang-2017-cancer-NF-kB-abstract]. Importantly, higher TMEM43 expression correlates with brain tumor malignancy, and suppression of TMEM43 in brain tumor cells inhibits tumor growth both in vitro and in vivo[jiang-2017-cancer-NF-kB-abstract]. These findings establish TMEM43 as a potential therapeutic target in EGFR-driven cancers.

The NF-κB connection extends to hepatocellular carcinoma (HCC), where Zhang and colleagues demonstrated that TMEM43 is highly expressed in HCC and promotes tumor development[zhang-2024-HCC-VDAC1-abstract]. Using RNA sequencing and The Cancer Genome Atlas databases, they identified an important regulatory relationship between TMEM43 and VDAC1 (voltage-dependent anion channel 1). TMEM43 affects HCC progression by regulating the ubiquitination level of VDAC1, with USP7 (ubiquitin-specific protease 7) participating in tumor growth through this TMEM43-dependent pathway[zhang-2024-HCC-VDAC1-abstract]. Absence of TMEM43 in cancer cells inhibits tumor development, suggesting that TMEM43 may have predictive value and represent a new treatment strategy for HCC[zhang-2024-HCC-VDAC1-abstract].

The cardiac relevance of NF-κB signaling was further highlighted by Gu and colleagues, who demonstrated that TMEM43 deficiency increases NF-κB activation in mouse hearts following pressure overload-induced hypertrophy[gu-2023-cardiac-hypertrophy-abstract]. In this context, TMEM43 appears to exert a protective role: reduced expression of TMEM43 during cardiac hypertrophy leads to worsening heart failure with deteriorating cardiac function, exacerbated hypertrophy, and increased fibrosis. Conversely, overexpression of TMEM43 in cardiomyocytes ameliorates the hypertrophic response and reduces NF-κB activation upon angiotensin II stimulation[gu-2023-cardiac-hypertrophy-abstract]. This suggests that TMEM43 may have context-dependent effects on NF-κB signaling, suppressing it in cardiac stress but mediating it in cancer cell proliferation.

Role in Brain Function: Astrocytic Gap Junction Networks

An emerging area of TMEM43 research concerns its function in the central nervous system, particularly in astrocytes. Kim and colleagues characterized TMEM43 as a pH-sensing cation channel that conducts transjunctional potentials between adjacent cells, further facilitating electrical couplings of gap junctions[kim-2023-astrocyte-memory-preprint]. This work, which represents the first direct characterization of TMEM43 function in the brain, demonstrated that the protein actively participates in gap junction networks of the hippocampus.

Studies of TMEM43 knockout mice revealed several hippocampal abnormalities: decreased astrocytic dye diffusion indicating impaired gap junction communication, decreased potassium buffering capacity, and increased neuronal excitability[kim-2023-astrocyte-memory-preprint]. These physiological changes were accompanied by alterations in the AMPA/NMDA receptor ratio and disrupted long-term potentiation (LTP), a cellular mechanism considered the neural substrate of memory formation[kim-2023-astrocyte-memory-preprint].

Critically, the electrophysiological changes in knockout mice led to a disturbance in memory retrieval, which could be rescued by TMEM43 overexpression[kim-2023-astrocyte-memory-preprint]. These results indicate that TMEM43 actively participates in gap junction networks of the hippocampus to prevent neurons from hyperexcitability, which is critical for memory retrieval. This work expands our understanding of TMEM43 beyond its originally characterized roles in cardiac and auditory systems to include a fundamental function in cognitive processes.

Disease Associations

Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 (ARVC5)

The p.S358L mutation in TMEM43 causes a fully penetrant, lethal form of arrhythmogenic cardiomyopathy. In the Newfoundland founder population, median life expectancy was 41 years in affected males compared to 71 years in affected females (relative risk 6.8), demonstrating significant sex influence on disease severity[merner-2008-ARVC5-abstract]. The mutation is of European origin, estimated to be 1300-1500 years old, and has been identified in families from Newfoundland, Germany, Denmark, the UK, and the USA, all sharing a common ancestral haplotype[milting-2014-european-founder-abstract].

Interestingly, germline Luma null mice are viable and exhibit normal cardiac function, and Luma S358L knock-in mice also display normal cardiac function and morphology[stroud-2018-mouse-knockout-abstract]. These findings suggest either species-specific differences in LUMA function or the requirement for additional factors to manifest the disease phenotype in mice, representing an important area for continued investigation.

Emery-Dreifuss Muscular Dystrophy-Related Myopathy

Mutations in TMEM43 have been identified in patients with EDMD-related myopathy. Liang and colleagues identified two heterozygous missense mutations, p.E85K and p.I91V, in patients presenting with muscular dystrophy, joint contractures, and cardiomyopathy with conduction defects[liang-2011-EDMD-abstract]. The p.E85K mutation causes failure of LUMA oligomerization and reduces nuclear staining with aggregation of emerin and SUN2, leading to abnormally shaped nuclei[liang-2011-EDMD-abstract].

Auditory Neuropathy Spectrum Disorder (ANSD)

The p.R372X nonsense mutation in TMEM43 causes autosomal dominant late-onset progressive ANSD, characterized by inability to discriminate speech despite preserved sensitivity to sound[jang-2021-ANSD-summary]. This mutation was identified in two large Asian families (Chinese and Korean) through linkage analysis and exome sequencing. Unlike the cardiac phenotype of the p.S358L mutation, ANSD patients with p.R372X show no cardiac abnormalities, demonstrating pleiotropy with mutation-specific phenotypes[jang-2021-ANSD-summary].

Knock-in mice with the p.R372X variant recapitulate progressive hearing loss with onset at 5-6 months of age (equivalent to human twenties). Morphological analysis reveals narrowed inner border cells in GLSs without significant hair cell loss or spiral ganglion neuron changes[jang-2021-ANSD-summary]. Based on the mechanistic understanding that the primary damage is restricted to GLSs rather than hair cells or neurons, cochlear implantation was successfully performed on affected patients, with rapid restoration of speech discrimination ability[jang-2021-ANSD-summary].

Experimental Evidence Summary

The functions of TMEM43 have been established through multiple lines of experimental evidence:

1. Genetic evidence: Human mutations cause ARVC5, EDMD-related myopathy, and ANSD with clear genotype-phenotype correlations[merner-2008-ARVC5-abstract][liang-2011-EDMD-abstract][jang-2021-ANSD-summary]

2. Biochemical evidence: Co-immunoprecipitation and proximity ligation assays demonstrate physical interactions with emerin, lamins, SUN2, Cx26, Cx30, Cx43, and TASK-1[liang-2011-EDMD-abstract][jang-2021-ANSD-summary][jang-2021-TASK1-abstract]

3. Electrophysiological evidence: Whole-cell patch clamp recordings show TMEM43-dependent passive conductance currents in cochlear GLSs; single-channel recordings from reconstituted protein confirm pore-forming capability[kang-2024-TMEM-ion-channels-summary][jang-2021-ANSD-summary]

4. Biophysical evidence: Atomic force microscopy demonstrates increased nuclear stiffness in cells carrying the p.S358L mutation[milting-2014-european-founder-abstract]

5. Animal model evidence: Knock-in mice with p.R372X mutation recapitulate progressive hearing loss with GLS-specific morphological and electrophysiological defects[jang-2021-ANSD-summary]

6. Cell biology evidence: Mutant TMEM43 disrupts localization of intercalated disc proteins (ZO-1, plakoglobin, α-catenin), alters Cx43 phosphorylation, reduces gap junction dye transfer, and decreases conduction velocity[siragam-2014-ARVC-cell-abstract]

7. Cancer biology evidence: High throughput screening identified TMEM43 as critical for EGFR-induced NF-κB activation; TMEM43 knockdown inhibits tumor growth in vitro and in vivo[jiang-2017-cancer-NF-kB-abstract]; TMEM43 regulates VDAC1 ubiquitination in hepatocellular carcinoma[zhang-2024-HCC-VDAC1-abstract]

8. Neurobiology evidence: TMEM43 knockout mice show decreased astrocytic dye diffusion, impaired potassium buffering, increased neuronal excitability, altered LTP, and memory retrieval deficits that can be rescued by TMEM43 overexpression[kim-2023-astrocyte-memory-preprint]

Open Questions

Several important questions regarding TMEM43 function remain unresolved:

1. High-resolution structure: No experimental three-dimensional structure of TMEM43 has been determined. Cryo-EM or crystal structure analysis is needed to understand the ion conduction pathway, gating mechanism, and interaction interfaces with partner proteins.

2. Species-specific differences: Why do Luma knockout mice and S358L knock-in mice show normal cardiac function while humans with the same mutation develop lethal cardiomyopathy? Are there modifier genes, environmental factors, or species-specific mechanical stresses that explain this discrepancy?

3. Tissue-specific localization: What determines whether TMEM43 localizes to the nuclear envelope, plasma membrane, or intercalated discs in different cell types? Are there tissue-specific post-translational modifications or binding partners?

4. Ion channel versus scaffold function: Is TMEM43's primary function as an ion channel, or does it serve primarily as a scaffold for gap junction protein complexes? Can these functions be separated genetically?

5. Mutation-specific mechanisms: Why do different TMEM43 mutations cause distinct diseases (cardiac vs. muscular vs. auditory phenotypes)? The p.S358L and p.R372X mutations affect different domains - how do their molecular effects differ?

6. Late-onset progressive phenotype: What triggers the progressive nature of both ARVC5 and ANSD? Is there age-dependent reduction in passive conductance current, accumulation of damage, or decline in compensatory mechanisms?

7. Therapeutic opportunities: Could TMEM43 or its interacting partners serve as therapeutic targets? The successful cochlear implantation in ANSD patients suggests that understanding cellular pathology can guide treatment - are there analogous approaches for cardiac disease?

8. Context-dependent NF-κB effects: How does TMEM43 suppress NF-κB activation in cardiomyocytes under stress while mediating EGFR-induced NF-κB activation in cancer cells? Are there tissue-specific interacting partners or post-translational modifications that determine this functional switch?

9. Cancer therapeutic potential: Given that TMEM43 knockdown inhibits tumor growth and its expression correlates with tumor malignancy, could TMEM43 inhibitors be developed as cancer therapeutics? What would be the cardiac side effects given TMEM43's protective role in cardiac hypertrophy?

10. Cognitive function in disease: Do patients with ARVC5 or other TMEM43 mutations exhibit subtle cognitive or memory deficits? The hippocampal findings from mouse studies suggest potential CNS effects that have not been systematically evaluated in human patients.

References

• merner-2008-ARVC5: Merner ND, Hodgkinson KA, Haywood AFM, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82(4):809-21. PMID: 18313022. DOI: 10.1016/j.ajhg.2008.01.010

• jang-2021-ANSD: Jang MW, Oh DY, Yi E, et al. A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder. Proc Natl Acad Sci USA. 2021;118(22):e2019681118. PMID: 34050020. DOI: 10.1073/pnas.2019681118

• kang-2024-TMEM-ion-channels: Kang H, Lee CJ. Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles. Exp Mol Med. 2024;56(4):850-860. PMID: 38556553. DOI: 10.1038/s12276-024-01206-1

• liang-2011-EDMD: Liang WC, Mitsuhashi H, Keduka E, et al. TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy. Ann Neurol. 2011;69(6):1005-13. PMID: 21391237. DOI: 10.1002/ana.22338

• franke-2014-intercalated-disc: Franke WW, Dörflinger Y, Kuhn C, et al. Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks. Cell Tissue Res. 2014;357(1):159-72. PMID: 24770932. DOI: 10.1007/s00441-014-1865-1

• stroud-2018-mouse-knockout: Stroud MJ, Fang X, Zhang J, et al. Luma is not essential for murine cardiac development and function. Cardiovasc Res. 2018;114(3):378-388. PMID: 29040414. DOI: 10.1093/cvr/cvx205

• siragam-2014-ARVC-cell: Siragam V, Cui X, Masse S, et al. TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. PLoS One. 2014;9(10):e109128. PMID: 25343256. DOI: 10.1371/journal.pone.0109128

• meinke-2011-LINC-complex: Meinke P, Nguyen TD, Wehnert MS. The LINC complex and human disease. Biochem Soc Trans. 2011;39(6):1693-7. PMID: 22103509. DOI: 10.1042/BST20110658

• milting-2014-european-founder: Milting H, Klauke B, Christensen AH, et al. The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. Eur Heart J. 2014;36(14):872-81. PMID: 24598986. DOI: 10.1093/eurheartj/ehu077

• jang-2021-TASK1: Jang MW, Kim TY, Sharma K, et al. A Deafness Associated Protein TMEM43 Interacts with KCNK3 (TASK-1) Two-pore Domain K(K2P) Channel in the Cochlea. Exp Neurobiol. 2021;30(5):319-328. PMID: 34737237. DOI: 10.5607/en21028

• lombardi-2011-wnt-signaling: Lombardi R, Marian AJ. Molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy: a disease of cardiac stem cells. Pediatr Cardiol. 2011;32(3):360-5. PMID: 21267716. DOI: 10.1007/s00246-011-9890-2

• orgil-2025-TMEM43-review: Orgil BO, Spaulding MS, Smith HP, et al. Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases. Int J Mol Sci. 2025;26(14):6856. PMID: 40725103. DOI: 10.3390/ijms26146856

• jiang-2017-cancer-NF-kB: Jiang C, Zhu Y, Zhou Z, et al. TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-κB activation and tumor progression. Oncogene. 2017;36(20):2813-2823. PMID: 27991920. DOI: 10.1038/onc.2016.430

• zhang-2024-HCC-VDAC1: Zhang N, Wang F, Yang X, et al. TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination. Transl Gastroenterol Hepatol. 2024;9:9. PMID: 38317750. PMCID: PMC10838614. DOI: 10.21037/tgh-23-108

• gu-2023-cardiac-hypertrophy: Gu Y, Yao YR, Ding Y, Zhang XW. Reduced expression of transmembrane protein 43 during cardiac hypertrophy leads to worsening heart failure in mice. Exp Biol Med. 2023;248(17):1437-1445. PMID: 37697676. PMCID: PMC10666727. DOI: 10.1177/15353702231191111

• kim-2023-astrocyte-memory: Kim TY, Bhattacharya A, et al. Astrocytic Gapjinc (TMEM43) modulates gap junction networks by facilitating transjunctional potentials. bioRxiv preprint. 2023. URL: https://www.biorxiv.org/content/10.1101/2022.11.08.515259v2 (Note: preprint, not yet peer-reviewed)

Citations

1. franke-2014-intercalated-disc-abstract.md
2. gu-2023-cardiac-hypertrophy-abstract.md
3. hodgkinson-2012-natural-history-abstract.md
4. jang-2021-ANSD-summary.md
5. jang-2021-TASK1-abstract.md
6. jiang-2017-cancer-NF-kB-abstract.md
7. kang-2024-TMEM-ion-channels-summary.md
8. kim-2023-astrocyte-memory-preprint.md
9. liang-2011-EDMD-abstract.md
10. lombardi-2011-wnt-signaling-abstract.md
11. meinke-2011-LINC-complex-abstract.md
12. merner-2008-ARVC5-abstract.md
13. milting-2014-european-founder-abstract.md
14. orgil-2025-TMEM43-review-abstract.md
15. siragam-2014-ARVC-cell-abstract.md
16. stroud-2018-mouse-knockout-abstract.md
17. zhang-2024-HCC-VDAC1-abstract.md
18. zink-2022-zebrafish-abstract.md

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan
We verified the target identity (UniProt Q9BTV4; human TMEM43/LUMA), gathered recent literature (2023–2024) and authoritative reviews, extracted functional and mechanistic evidence, compiled clinical relevance and implementation, and synthesized a structured, fully cited research report.

Executive summary
TMEM43 (LUMA) encodes a four-pass integral membrane protein primarily localized to the inner nuclear membrane (INM), where it interacts with lamins and emerin and contributes to nuclear-envelope integrity and mechanotransduction. Disease-causing variants—most notably the founder p.S358L—cause arrhythmogenic right ventricular cardiomyopathy (ARVC5) with high arrhythmic risk; additional variants affect skeletal muscle (EDMD-like) and auditory function (autosomal‑dominant auditory neuropathy). Recent 2023–2024 work refined burden and penetrance estimates in ACM cohorts, expanded mechanistic insight into signaling (GSK3β/Wnt; NF‑κB–TGFβ; DDR), and introduced translational concepts including AAV-mediated WT‑TMEM43 replacement and small-molecule pathway modulation; cancer studies implicated a USP7–TMEM43–VDAC1 axis in HCC. Key statistics: ARVC prevalence ~1/1000–1/5000; SCD incidence ~0.7%/year without ICD; p.S358L onset medians ~32 years in males and ~44 in females in curated cohorts (Padua), with enrichment of TMEM43 among non‑desmosomal ACM genes (≈3.8‑fold) (mistrulli2024cardiomyopathyandsudden pages 10-11, marinas2024acomprehensiveanalysis pages 7-10).

1) Key concepts and definitions with current understanding
- Molecular identity and family/domains: TMEM43/LUMA is a conserved TMEM43-family protein with four transmembrane helices (PF07787; IPR012430), functioning as a structural/adapter component of the INM rather than as an enzyme or transporter (padillamejia2021evolutionanddiversification pages 11-13, shin2022molecularpathologyof pages 11-13).
- Subcellular localization: Predominant at the inner nuclear membrane and contiguous ER; in cardiomyocytes also detected at intercalated discs/adherens junctions; expressed in cochlear glia-like supporting cells (GLSs) (risato2024invivoapproaches pages 21-22, padillamejia2021evolutionanddiversification pages 11-13, niu2023usingzebrafishanimal pages 10-12).
- Core interactions and complexes: Interacts with emerin (EMD), lamins A/C, and SUN2, situating it within LINC-associated networks; tissue-specific interactions include connexins (Cx26/Cx30) and TASK‑1 in cochlear GLSs; studies also report VDAC1/2 relationships relevant to metabolism and cancer (risato2024invivoapproaches pages 21-22, orgil2025transmembraneprotein43 pages 2-4, zhang2024tmem43promotesthe pages 1-2).
- Primary biological role: Maintenance of nuclear-envelope integrity and mechanotransduction through lamina/emerin organization; haploinsufficiency activates DDR and drives late-onset pro‑fibrotic cardiomyopathy in mice; not a catalytic protein (shin2022molecularpathologyof pages 11-13, risato2024invivoapproaches pages 21-22).

2) Recent developments and latest research (priority to 2023–2024)
- TMEM43 as a putative channel vs structural role: A 2024 review grouped TMEM43 (“Gapjinc”) among TMEM proteins with ion-channel claims, but consensus primary role remains INM structural/adapter; electrophysiology remains tissue/context dependent and not canonical for nuclear-envelope TM proteins (kang2024transmembraneproteinswith pages 1-3).
- Mechanistic pathways in ACM: Preclinical models indicate S358L amplifies NF‑κB–TGFβ cascades and that inhibition of GSK3β rescues ARVC5 phenotypes in mice/vertebrate models, supporting Wnt/GSK3β involvement (risato2024invivoapproaches pages 21-22).
- Burden and penetrance: 2024 Padua analysis of non‑desmosomal ACM genes found TMEM43 rare P/LP variants enriched (~3.79‑fold), with curated p.S358L onset medians ~32 (male)/~44 (female) years and sex‑dependent penetrance; most other TMEM43 variants remain VUS (marinas2024acomprehensiveanalysis pages 7-10).
- Clinical risk framing: 2024 SCD review emphasizes that, unlike many ARVC genes with incomplete penetrance, TMEM43 p.S358L is fully penetrant and confers high arrhythmic risk; ARVC prevalence ~1/1000–1/5000 and SCD incidence ~0.7%/year in patients without ICD (mistrulli2024cardiomyopathyandsudden pages 10-11).
- Cancer biology: 2024 HCC study shows USP7 stabilizes TMEM43, which upregulates/activates VDAC1 to promote tumor progression; suggests an actionable USP7–TMEM43–VDAC1 axis (zhang2024tmem43promotesthe pages 1-2).
- Animal/iPSC models: Zebrafish and mouse models (including S358L knock‑in/overexpression) and human iPSC systems delineate conduction/gap-junction and nuclear-envelope defects; zebrafish screens identified GSK3β inhibition as disease-modifying (niu2023usingzebrafishanimal pages 10-12, risato2024invivoapproaches pages 21-22).

3) Current applications and real-world implementations
- Genetic testing/panels: TMEM43 is included among non‑desmosomal ACM genes with strong evidence; positive findings guide family cascade testing and lifestyle modification (avoid high-intensity exercise), with ICD consideration based on phenotype plus recognition of genotype‑specific risk (marinas2024acomprehensiveanalysis pages 7-10, mistrulli2024cardiomyopathyandsudden pages 10-11).
- Device cohorts: A 2024 tertiary-center device cohort reported TMEM43 among the more frequent positive genetic findings (≈11% of positives across a mixed arrhythmia population), illustrating real-world detection in arrhythmia/device candidates (goanta2024unexpectedgenetictwists pages 6-8).
- Imaging and risk stratification: CMR and arrhythmia history remain central to SCD risk assessment; genotype (e.g., TMEM43) adds context to risk but is not yet an independent risk predictor across all ARVC forms (mistrulli2024cardiomyopathyandsudden pages 10-11).

4) Expert opinions and analysis from authoritative sources
- Nuclear-envelope disease frameworks emphasize dual mechanisms—mechanotransduction defects and gene-expression programs—as relevant to TMEM43-linked cardiomyopathy; DDR activation and stress signaling are prominent in TMEM43 insufficiency (shin2022molecularpathologyof pages 11-13).
- Evolutionary and NE-proteome perspectives place TMEM43 among metazoan NE proteins linked to muscle/cardiac disease, interacting with lamins/emerin and LINC (padillamejia2021evolutionanddiversification pages 11-13).
- Contemporary ARVC genetics reviews and in vivo model syntheses underscore TMEM43, PLN, and DES as non-desmosomal genes with the most robust gene‑disease evidence (risato2024invivoapproaches pages 21-22, mistrulli2024cardiomyopathyandsudden pages 10-11).

5) Relevant statistics and data from recent studies
- ARVC epidemiology and outcomes: Prevalence ~1/1000–1/5000; SCD incidence ~0.7%/year in ARVC patients without ICD; lower SCD incidence among ICD recipients (mistrulli2024cardiomyopathyandsudden pages 10-11).
- TMEM43 burden/penetrance: Enrichment ratio ~3.79 for rare P/LP TMEM43 variants in select non‑desmosomal ACM cohorts; p.S358L median onset ~32 years (males) and ~44 years (females), with sex‑dependent penetrance curves; other variants mostly VUS (marinas2024acomprehensiveanalysis pages 7-10).
- Real-world testing: In a small 2018–2023 tertiary device cohort, TMEM43 comprised ~11% of positive genetic tests across heterogeneous arrhythmia/device patients (goanta2024unexpectedgenetictwists pages 6-8).

Functional annotation: mechanism, location, and pathways
- Cellular location of function: TMEM43 acts mainly at the inner nuclear membrane to scaffold lamins/emerin and connect to LINC-associated mechanotransduction, with additional roles at intercalated discs (cardiomyocyte junctional complexes) and in cochlear GLSs (gap‑junction milieu) (risato2024invivoapproaches pages 21-22, padillamejia2021evolutionanddiversification pages 11-13, niu2023usingzebrafishanimal pages 10-12).
- Interactions and complexes: Emerin (EMD) and lamin A/C interactions influence emerin distribution and NE stability; SUN2/LINC association supports nuclear–cytoskeletal force transmission; tissue-specific associations include connexins Cx26/Cx30 and TASK‑1; VDAC1/2 associations emerge in mutant/cancer contexts (risato2024invivoapproaches pages 21-22, orgil2025transmembraneprotein43 pages 2-4, zhang2024tmem43promotesthe pages 1-2).
- Mechanistic role in signaling: In ARVC5 models, S358L augments NF‑κB–TGFβ signaling and GSK3β/Wnt dysregulation; haploinsufficiency activates DDR leading to senescence and pro‑fibrotic cardiomyopathy; HCC data implicate USP7‑dependent stabilization of TMEM43 driving VDAC1 activation; auditory models suggest PI3K‑AKT and calcium signaling changes in GLS function (risato2024invivoapproaches pages 21-22, zhang2024tmem43promotesthe pages 1-2, niu2023usingzebrafishanimal pages 10-12).
- Is TMEM43 an ion channel? Evidence remains insufficient to define TMEM43 as a canonical ion channel in heart; 2024 review groups TMEM43 within TMEM channels (“Gapjinc”), but prevailing data support a structural/adapter role with potential indirect modulation of channel complexes (e.g., connexins, TASK‑1) (kang2024transmembraneproteinswith pages 1-3).

Pathogenic variants and phenotypes
- ARVC5 (p.S358L): Founder variant with high/complete penetrance and severe arrhythmic risk; increases nuclear stiffness, disrupts intercalated-disc and signaling pathways; age‑of‑onset and sex‑specific penetrance refined by 2024 analyses; founder effects documented in multiple populations (risato2024invivoapproaches pages 21-22, marinas2024acomprehensiveanalysis pages 7-10).
- EDMD-like myopathy: Missense variants such as p.E85K and p.I91V reported in EDMD phenotypes, linked to emerin mislocalization and LINC disruption in model systems (risato2024invivoapproaches pages 21-22, orgil2025transmembraneprotein43 pages 2-4).
- Auditory neuropathy spectrum disorder (ANSD): Truncating variants (e.g., Arg372Ter) associate with autosomal‑dominant ANSD; models show impaired gap‑junction communication and altered GLS signaling (orgil2025transmembraneprotein43 pages 19-21).
- Cancer associations: Overexpression or stabilization of TMEM43 promotes HCC progression via VDAC1 activation (USP7-mediated), suggesting an oncogenic module in specific contexts (zhang2024tmem43promotesthe pages 1-2).

Models, interventions, and translational directions
- Models: S358L knock‑in and transgenic mice show ARVC5 hallmarks; zebrafish overexpression/KO models recapitulate conduction and structural phenotypes; iPSC‑derived cardiomyocytes and cochlear GLSs model human cell-type phenotypes (risato2024invivoapproaches pages 21-22, niu2023usingzebrafishanimal pages 10-12, orgil2025transmembraneprotein43 pages 19-21).
- Small-molecule pathway modulation: GSK3β inhibition improves function and survival in ARVC5 models, supporting canonical Wnt involvement; ACE inhibition (enalapril) improved function and delayed mortality in preclinical ARVC5 mice (risato2024invivoapproaches pages 21-22).
- Gene therapy: Preclinical AAV‑mediated WT‑TMEM43 overexpression ameliorated S358L-driven phenotypes in mice, highlighting a replacement strategy; clinical trials have not yet been reported for TMEM43 (orgil2025transmembraneprotein43 pages 16-17, risato2024invivoapproaches pages 21-22).

Clinical implementation and guidelines
- Testing and counseling: TMEM43 is recognized among non‑desmosomal ARVC genes with robust disease association; cascade screening, exercise restriction, and ICD decisions are informed by phenotype and, for p.S358L, elevated arrhythmic risk (marinas2024acomprehensiveanalysis pages 7-10, mistrulli2024cardiomyopathyandsudden pages 10-11).
- Risk stratification: Genetic background alone is not universally an independent SCD predictor in ARVC, but TMEM43 p.S358L is an exception with high risk; CMR fibrosis/fatty infiltration and arrhythmic history remain crucial (mistrulli2024cardiomyopathyandsudden pages 10-11).

Quick-reference summary table
| Aspect | Current understanding (1–2 sentences) | 2023–2024 updates | Key sources (author/year + DOI where available) |
|---|---|---|---|
| Identity / domains | TMEM43 (LUMA) is a conserved ~43 kDa integral membrane protein belonging to the TMEM43 family with four transmembrane helices; annotated domains include TMEM43_fam (IPR012430) / PF07787. | Structural models and proteomic annotation reinforce a 4-TM topology with oligomerization interfaces and predicted post‑translational modification sites; some analyses propose an intramembrane pore-like region (TM3/Loop2). | Padilla‑Mejia 2021 https://doi.org/10.1080/19491034.2021.1874135 (padillamejia2021evolutionanddiversification pages 11-13), Kang 2024 https://doi.org/10.1038/s12276-024-01206-1 (kang2024transmembraneproteinswith pages 1-3) |
| Subcellular localization | Predominantly localized to the inner nuclear membrane (INM) and endoplasmic reticulum; reported additional localization to cardiac intercalated discs and adherens junctions in cardiomyocytes and to cochlear glial support cells. | Recent proteomic and imaging studies (animal and cell models) confirm INM targeting via lamin interactions and document functional presence at intercalated discs and cochlear GLSs in 2023–2024 models. | Padilla‑Mejia 2021 (padillamejia2021evolutionanddiversification pages 11-13), Risato 2024 https://doi.org/10.3390/cells13151264 (risato2024invivoapproaches pages 21-22), Niu 2023 https://doi.org/10.3390/ijms24044106 (niu2023usingzebrafishanimal pages 10-12) |
| Interacting partners | Biochemical and cell biology studies report interactions with emerin (EMD), lamin A/C, SUN proteins (LINC complex components); additional reported partners include VDAC1/2, connexins (Cx26/Cx30) and TASK‑1 in tissue-specific contexts. | 2023–2024 IP/proximity studies and cancer work show altered VDAC binding for S358L and a TMEM43–VDAC1 regulatory axis (USP7-mediated) in HCC; cochlear models show connexin complex perturbation. | Zhang 2024 https://doi.org/10.21037/tgh-23-108 (zhang2024tmem43promotesthe pages 1-2), Orgil 2025 (TMEM43 review extract) (orgil2025transmembraneprotein43 pages 2-4), Kang 2024 (kang2024transmembraneproteinswith pages 1-3) |
| Primary molecular / biological functions | Functions primarily as an INM structural/adapter protein that helps maintain nuclear envelope integrity, organize emerin/lamina interactions, and contribute to mechanotransduction; not classified as an enzyme or canonical transporter. | Functional studies (haploinsufficiency, KO) implicate TMEM43 in maintaining NE stability and preventing activation of DNA damage responses; in cochlea, TMEM43 influences glial K+ handling/gap‑junction communication. | Shin & Worman 2022 https://doi.org/10.1146/annurev-pathol-042220-034240 (shin2022molecularpathologyof pages 11-13), Risato 2024 (risato2024invivoapproaches pages 21-22), Niu 2023 (niu2023usingzebrafishanimal pages 10-12) |
| Pathways implicated | Linked mechanistically to LINC/mechanotransduction pathways, and reported to influence Wnt/GSK3β, NF‑κB–TGFβ signaling, DDR (DNA damage response), lipid metabolism and ferroptosis-related processes. | 2023–2024 data: S358L models amplify NF‑κB–TGFβ signaling and Wnt/GSK3β modulation (GSK3β inhibitors rescue phenotypes in models); cancer studies implicate USP7–TMEM43–VDAC1 axis (VDAC regulation) in tumor progression. | Zheng et al. (cited in Risato) / Padrón‑Barthe 2019 (risato2024invivoapproaches pages 21-22), Zhang 2024 (zhang2024tmem43promotesthe pages 1-2), Kang 2024 (kang2024transmembraneproteinswith pages 1-3) |
| Pathogenic variants & penetrance | The founder missense p.S358L (c.1073C>T) causes ARVC5 with marked arrhythmic risk; other missense (e.g., p.E85K, p.I91V) reported in EDMD-like myopathies; truncating/nonsense variants linked to auditory neuropathy phenotypes. | Cohort re-analyses (2023–2024) refine age-of-onset/penetrance estimates for p.S358L (median onset ~32 males/44 females) and confirm founder effects; numerous other rare variants remain VUS or require functional validation. | Marinas 2024 https://doi.org/10.3390/ijms25116267 (marinas2024acomprehensiveanalysis pages 7-10), Risato 2024 (risato2024invivoapproaches pages 21-22), Mistrulli 2024 https://doi.org/10.3390/biomedicines12071602 (mistrulli2024cardiomyopathyandsudden pages 10-11) |
| Disease areas (cardiac, neuromuscular, auditory, cancer) | Clinically linked to arrhythmogenic cardiomyopathy/ARVC (notably ARVC5), Emery–Dreifuss–like myopathies, autosomal‑dominant auditory neuropathy (ANSD) and reported associations with cancers (HCC, pancreatic). | 2023–2024 model and clinical studies strengthened cardiac and auditory mechanistic links; 2024 reports implicate TMEM43 in HCC via VDAC1/USP7 signaling and in tumor cell survival. | Marinas 2024 (marinas2024acomprehensiveanalysis pages 7-10), Zhang 2024 (zhang2024tmem43promotesthe pages 1-2), Niu 2023 (niu2023usingzebrafishanimal pages 10-12) |
| Models & mechanistic insights | Experimental systems include S358L knock‑in and overexpression mouse models, zebrafish transgenic/KO models, TMEM43 KO/haploinsufficient mice, and human iPSC-derived cardiomyocytes and cochlear GLSs. | 2023 knock‑in mice show cardiac, intestinal and metabolic effects; zebrafish and iPSC GLS models (2023–2024) reveal conduction/gap-junction and ionic homeostasis defects; AAV-mediated WT‑TMEM43 rescue shown preclinically. | Orgil/Orgil review extracts (orgil2025transmembraneprotein43 pages 1-2), Niu 2023 (niu2023usingzebrafishanimal pages 10-12), Risato 2024 (risato2024invivoapproaches pages 21-22) |
| Therapeutic concepts / clinical implementation | No approved TMEM43‑targeted therapies yet; preclinical strategies include AAV-mediated WT‑TMEM43 gene delivery and pathway-targeting small molecules (e.g., GSK3β inhibitors) that modulate downstream signaling. | Preclinical AAV‑WT rescue (mouse) and small-molecule rescue in zebrafish/other ACM models reported (proof‑of‑concept); clinical guidelines increasingly recognize TMEM43 among non‑desmosomal genes warranting surveillance. | Risato 2024 (risato2024invivoapproaches pages 21-22), Mistrulli 2024 (mistrulli2024cardiomyopathyandsudden pages 10-11), Orgil review extracts (orgil2025transmembraneprotein43 pages 2-4) |
| Cohort / burden analyses & guideline placement | TMEM43 variants are rare overall but p.S358L is a population/founder variant with strong disease association; analyses show enrichment of TMEM43 among non‑desmosomal ACM genes in some cohorts. | 2024 Padua cohort and other reappraisals report ~3.8‑fold enrichment for TMEM43 rare P/LP variants in selected ACM cohorts and provide age/penetrance estimates; 2023 ESC/guideline discussions place TMEM43 among a small set of non‑desmosomal genes with substantive evidence. | Marinas 2024 https://doi.org/10.3390/ijms25116267 (marinas2024acomprehensiveanalysis pages 7-10), Mistrulli 2024 (mistrulli2024cardiomyopathyandsudden pages 10-11) |

Table: Concise table summarizing TMEM43 identity, localization, interactions, function, disease links, models, therapeutic concepts, and 2023–2024 updates with primary sources for quick reference.

URLs (representative recent sources)
- Kang 2024, Experimental & Molecular Medicine: https://doi.org/10.1038/s12276-024-01206-1 (TMEM43/“Gapjinc”) (kang2024transmembraneproteinswith pages 1-3)
- Zhang 2024, Translational Gastroenterology and Hepatology: https://doi.org/10.21037/tgh-23-108 (USP7–TMEM43–VDAC1 in HCC) (zhang2024tmem43promotesthe pages 1-2)
- Marinas 2024, Int J Mol Sci: https://doi.org/10.3390/ijms25116267 (Padua cohort, non‑desmosomal ACM burden; TMEM43 penetrance) (marinas2024acomprehensiveanalysis pages 7-10)
- Mistrulli 2024, Biomedicines: https://doi.org/10.3390/biomedicines12071602 (ARVC epidemiology; TMEM43 p.S358L risk) (mistrulli2024cardiomyopathyandsudden pages 10-11)
- Risato 2024, Cells: https://doi.org/10.3390/cells13151264 (in vivo ACM models; TMEM43 citations) (risato2024invivoapproaches pages 21-22)
- Niu 2023, Int J Mol Sci: https://doi.org/10.3390/ijms24044106 (zebrafish ACM models; GSK3β inhibitor rescue) (niu2023usingzebrafishanimal pages 10-12)
- Shin & Worman 2022, Annu Rev Pathol: https://doi.org/10.1146/annurev-pathol-042220-034240 (NE disease mechanisms) (shin2022molecularpathologyof pages 11-13)
- Padilla‑Mejia 2021, Nucleus: https://doi.org/10.1080/19491034.2021.1874135 (evolution/NE disease mapping; TMEM43 interactions) (padillamejia2021evolutionanddiversification pages 11-13)
- Goanta 2024, J Clin Med: https://doi.org/10.3390/jcm13133801 (device cohort; TMEM43 frequency among positives) (goanta2024unexpectedgenetictwists pages 6-8)

Limitations and open questions
- Ion-channel claims for TMEM43 remain debated and tissue‑specific; definitive electrophysiology in cardiomyocytes is lacking compared to strong INM structural evidence (kang2024transmembraneproteinswith pages 1-3).
- Many TMEM43 variants remain VUS; functional validation is needed to clarify pathogenicity and mechanism (marinas2024acomprehensiveanalysis pages 7-10).
- Translational therapies (AAV WT‑TMEM43, GSK3β inhibitors) are preclinical; no human trials yet specifically targeting TMEM43 (risato2024invivoapproaches pages 21-22).

Verification of target identity and organism
All data herein refer to human TMEM43 (UniProt Q9BTV4; LUMA), a TMEM43-family protein localized to the INM/ER and junctional structures, consistent with UniProt domains and family membership. No conflicting gene-symbol usage was used (padillamejia2021evolutionanddiversification pages 11-13, shin2022molecularpathologyof pages 11-13, risato2024invivoapproaches pages 21-22).

References

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TMEM43 (LUMA) – Function, Localization, and Biological Role

Overview and Key Characteristics

Transmembrane protein 43 (TMEM43), also known as LUMA, is a highly conserved 45 kDa protein that localizes to multiple cellular membranes. It was initially identified as an integral membrane component of the nuclear envelope (specifically the inner nuclear membrane, INM) (pmc.ncbi.nlm.nih.gov). Recent studies revealed TMEM43 is also present at certain cell–cell junctions, including the adherens junctions of epithelial cells and the composite junctions of cardiac intercalated discs (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In cardiomyocytes, TMEM43 has been observed predominantly at the intercalated disc and sarcolemma (the plasma membrane of muscle cells) rather than the nucleus (pmc.ncbi.nlm.nih.gov). Consistently, TMEM43 is described as a “widespread plaque protein” found in the INM, endoplasmic reticulum (ER), and zonula adherens junctions across many tissues (pmc.ncbi.nlm.nih.gov). TMEM43’s dual presence in the nuclear envelope and at cell junctions suggests it plays a role in maintaining structural connectivity from the cell periphery to the nucleus.

TMEM43 contains multiple hydrophobic segments and is predicted to span the membrane four times (a tetraspan membrane protein) (pubmed.ncbi.nlm.nih.gov). Both the N- and C-termini face the cytoplasmic side (or nucleoplasmic side at the INM) according to topology predictions, positioning TMEM43 to interact with cytoskeletal and nuclear components inside the cell. TMEM43 is expressed widely in human tissues, with highest mRNA levels reported in placenta, and significant levels in heart, skin, ovary and other organs (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This broad expression pattern, combined with its high sequence conservation from yeast to humans (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), underscores a fundamental cellular function.

Subcellular Localization and Structural Interactions

Inner Nuclear Membrane: At the nuclear periphery, TMEM43 resides in the inner nuclear membrane where it interacts with key components of the nuclear lamina. It has been shown to bind lamin A/C, lamin B1, SUN2, and emerin – all important proteins of the nuclear envelope (pmc.ncbi.nlm.nih.gov). Through these interactions, TMEM43 helps anchor the nuclear lamina to the membrane. In particular, TMEM43 plays a critical role in the correct localization of emerin at the INM (pmc.ncbi.nlm.nih.gov). Emerin is a nuclear membrane protein that connects the lamina to the cytoskeleton and contributes to gene regulation; normally, emerin’s retention at the INM depends on binding lamin A/C (pmc.ncbi.nlm.nih.gov). TMEM43 appears to stabilize emerin in the nuclear envelope, as loss of TMEM43 causes emerin to mislocalize (pmc.ncbi.nlm.nih.gov). Consistent with this, Bengtsson & Otto (2008) found that TMEM43 (LUMA) directly interacts with emerin and influences emerin’s distribution in the nucleus (pmc.ncbi.nlm.nih.gov). By helping attach the lamina (via lamin–emerin connections) to the inner membrane, TMEM43 contributes to nuclear structural integrity and shape. Indeed, partial loss of Tmem43 in mouse hearts triggers a DNA damage response (DDR) and premature cellular senescence, suggesting compromised nuclear integrity when TMEM43 is insufficient (pmc.ncbi.nlm.nih.gov).

Cell–Cell Junctions: Outside the nucleus, TMEM43 is found in the plaques of cell junctions that experience mechanical stress. Franke et al. (2014) discovered that TMEM43 is a constitutive component of the cytoplasmic plaques at zonula adherens junctions in various epithelia and at the composite junctions in cardiac intercalated discs (pubmed.ncbi.nlm.nih.gov). In these locations, TMEM43 co-localizes with other junctional proteins (such as cadherins, catenins, desmosomal proteins) and was notably absent from the nuclear envelope in those cells (pubmed.ncbi.nlm.nih.gov). This finding overturned earlier assumptions that TMEM43 was only a nuclear protein, and firmly placed it as a structural component of cellular adhesion sites. In cardiomyocytes, intercalated discs contain three types of junctions – fascia adherens (anchoring actin filaments via N-cadherin and catenins), desmosomes (linking intermediate filaments via desmoplakin, plakoglobin, etc.), and gap junctions (for ionic coupling via connexins) (pmc.ncbi.nlm.nih.gov). TMEM43 (LUMA) localizes to the adherens and desmosomal regions of the intercalated disc (pubmed.ncbi.nlm.nih.gov), making it one of the proteins that connect the contractile apparatus of one cell to another. In line with this, Christensen et al. (2011) examined human cardiac tissue and found TMEM43 mainly at the sarcolemmal membrane, including intercellular junctions, with little or no signal at nuclei (pmc.ncbi.nlm.nih.gov). Thus, TMEM43 is present at multiple membrane systems: the nuclear envelope (INM and associated ER membrane) and the plasma membrane at sites of cell adhesion. This strategic localization positions TMEM43 as a linker between the nucleoskeleton and cytoskeleton, and between cells in a tissue (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Biological Function and Mechanosignaling Role

TMEM43’s primary function is structural and organizational – it contributes to the architecture of the nucleus and to intercellular connections, thereby maintaining tissue integrity. Because it spans membranes and binds structural proteins, TMEM43 is thought to facilitate mechanotransduction, the conversion of mechanical stimuli into biochemical signals (pmc.ncbi.nlm.nih.gov). Specifically, TMEM43 is implicated in the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, which physically couples the nuclear interior to the cytoskeleton (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). By bridging lamins and SUN2 at the inner nuclear membrane (components of LINC) (pmc.ncbi.nlm.nih.gov), TMEM43 helps transmit forces from the cytoskeleton to the nucleus. These forces can influence chromatin organization and gene expression programs in response to mechanical cues (pmc.ncbi.nlm.nih.gov). For example, mechanical strain on a cell can be conveyed through TMEM43-associated complexes to alter gene expression as part of the cell’s adaptation to stress (pmc.ncbi.nlm.nih.gov). In muscle cells, which endure repeated contraction-relaxation cycles, this mechanosensitive pathway is critical for adjusting gene expression to mechanical load (pmc.ncbi.nlm.nih.gov).

Consistent with a role in force transmission, TMEM43 interacts not only with nuclear lamina components but also with actin filaments. In immunoprecipitation experiments, TMEM43 was found in complex with β-actin, suggesting it anchors or associates with the actin cytoskeleton (pmc.ncbi.nlm.nih.gov). Notably, when the disease-causing mutant form TMEM43-S358L is expressed in mice, it shows reduced binding to emerin and actin, and a portion of the mutant protein mislocalizes to the cytoplasm (pmc.ncbi.nlm.nih.gov). The loss of these interactions coincides with activation of GSK-3β signaling in mutant hearts (pmc.ncbi.nlm.nih.gov). GSK-3β is a kinase involved in multiple pathways (including Wnt signaling), so its activation may reflect downstream consequences of a weakened nucleo-cytoskeletal linkage. These findings highlight that normal TMEM43 helps tether the cytoskeleton to the nuclear membrane, and that disrupting TMEM43 can perturb signaling pathways and cell structure.

At the intercalated disc, TMEM43 likely contributes to the strength and organization of cardiac cell–cell junctions. The intercalated disc is an essential structure for mechanical and electrical coupling between cardiomyocytes. By associating with adherens junction components (e.g. N-cadherin/catenin complex) and possibly desmosomal proteins, TMEM43 may stabilize the junctional plaque. Franke et al. observed that TMEM43 colocalizes with plakoglobin (JUP) and other junction markers at the intercalated disc (pubmed.ncbi.nlm.nih.gov), implying that TMEM43 is part of the protein network that links cadherin adhesion complexes to the cytoskeleton. This network ensures that contractile force is transmitted from one cell to the next and prevents cells from pulling apart during contraction. Loss of TMEM43 could therefore weaken cell–cell adhesion or alter the composition of junctional complexes. Indeed, there is evidence that TMEM43 influences the distribution of plakoglobin: in hearts of TMEM43 S358L mutant mice, plakoglobin was found aberrantly translocated into nuclei (away from the disc) (pmc.ncbi.nlm.nih.gov). This is significant because plakoglobin (γ-catenin) normally helps anchor desmosomes; its movement to the nucleus is associated with a suppression of Wnt/β-catenin signaling, a phenomenon seen in arrhythmogenic cardiomyopathies (pmc.ncbi.nlm.nih.gov). Thus, TMEM43’s integrity at the intercalated disc appears necessary to keep plakoglobin at the membrane and maintain proper Wnt signaling balance in cardiomyocytes.

In addition to structural roles, TMEM43 has been linked to ion channel regulation in certain cell types. Inner-ear studies indicate TMEM43 is important in cochlear supporting cells, which are glia-like cells connected by gap junctions. TMEM43 was found to physically interact with the gap-junction proteins Connexin26 and Connexin30 in these supporting cells (pmc.ncbi.nlm.nih.gov). By doing so, TMEM43 helps maintain the gap-junction mediated ionic coupling that is crucial for recycling potassium ions in the inner ear. A 2021 study demonstrated that a TMEM43 truncation mutant (p.Arg372Ter) disrupts passive K^+ currents in cochlear glial cells by impairing connexin function (pmc.ncbi.nlm.nih.gov). These glial gap junctions normally clear extracellular K^+ to sustain hair cell excitability; without functional TMEM43, the coupling is lost and hearing is compromised (pmc.ncbi.nlm.nih.gov). Separately, TMEM43 was also reported to interact with a two-pore K^+ channel (KCNK3) in the cochlea, suggesting a broader role in supporting the ion channels of these cells (pmc.ncbi.nlm.nih.gov). In summary, TMEM43 contributes to cellular communication – mechanical and electrical – by organizing membrane complexes (adherence junctions, gap junctions, and nuclear-cytoskeletal tethers).

Involvement in Signaling Pathways

While TMEM43 does not have known enzymatic activity, its position in cellular architecture allows it to influence several signaling pathways indirectly. One major pathway affected is the Wnt/β-catenin signaling pathway. Through its interaction with emerin and β-catenin-associated complexes, TMEM43 can modulate Wnt signaling outcomes in muscle cells (pmc.ncbi.nlm.nih.gov). Emerin, which TMEM43 helps localize, is known to bind and sequester β-catenin at the nuclear periphery, thereby repressing Wnt-driven gene transcription in cardiac and skeletal muscle (pmc.ncbi.nlm.nih.gov). If TMEM43 is lost or mutated, emerin’s function is altered, and β-catenin signaling can become dysregulated. In line with this, TMEM43 S358L mutant hearts showed reduced β-catenin levels and nuclear accumulation of plakoglobin (which can replace β-catenin in some transcriptional complexes) (pmc.ncbi.nlm.nih.gov). This suggests a shift toward Wnt signal suppression in the heart. Conversely, in the small intestine of the same TMEM43 mutant mice, researchers observed elevated β-catenin and cell proliferation (Ki-67), indicating heightened Wnt activity in gut epithelium (pmc.ncbi.nlm.nih.gov). Distinct tissues may thus respond differently to TMEM43 dysfunction, but it is clear TMEM43 is a node in the network that governs Wnt/β-catenin signaling and cell proliferation.

Another pathway tied to TMEM43 is the PPARγ pathway, which is involved in adipogenesis and metabolism. Interestingly, the promoter of the TMEM43 gene contains a response element for PPARγ (a lipid-activated transcription factor) (www.ncbi.nlm.nih.gov). TMEM43 has been identified as a potential target gene of PPARγ, linking it to fat metabolism and storage processes (pmc.ncbi.nlm.nih.gov). In support of this, a comprehensive study of hearts from ARVC patients showed that TMEM43 expression is associated with fibro-fatty changes: TMEM43 was upregulated in conjunction with adipogenic genes in diseased myocardium (pmc.ncbi.nlm.nih.gov). In a mouse model, the S358L mutation in TMEM43 led to diminished PPARγ activity in the heart (despite the heart accumulating fat) but paradoxically caused increased lipid absorption and PPARγ-related signaling in the intestine (pmc.ncbi.nlm.nih.gov). These findings hint that TMEM43 might normally help balance metabolic signaling between tissues, and that its mutation perturbs PPARγ-regulated pathways. Moreover, oxidative stress signals like oxidized LDL can activate PPARγ and have been linked to worse outcomes in ARVC patients with TMEM43 mutations (more fat infiltration and arrhythmias) (pmc.ncbi.nlm.nih.gov). This suggests TMEM43 is part of a pathophysiological loop where metabolic factors exacerbate cardiac dysfunction.

Inflammatory signaling pathways, such as NF-κB, are also influenced by TMEM43. Cell studies have shown that TMEM43 over-expression can activate the NF-κB pathway through EGFR (epidermal growth factor receptor) signaling (pmc.ncbi.nlm.nih.gov). In cancer cell models, TMEM43 was found to stabilize the pre-mRNA processing factor 3 (PRPF3), leading to enhanced NF-κB activity and promoting tumor cell survival and migration (pmc.ncbi.nlm.nih.gov). These data imply that TMEM43 can crosstalk with growth factor and transcriptional stress pathways, potentially by affecting how signals are transmitted to the nucleus. On the other hand, in certain contexts TMEM43 may protect cells: for instance, high TMEM43 expression in cardiomyocytes was reported to guard against sepsis-induced cardiac injury by inhibiting ferroptosis (an iron-dependent cell death) through an NF-κB-related mechanism (pmc.ncbi.nlm.nih.gov). Additionally, transcriptomic studies in human placenta have linked TMEM43 upregulation to inflammatory pathways and cognitive impairment in preterm infants, suggesting TMEM43-mediated NF-κB activation might have developmental effects (pmc.ncbi.nlm.nih.gov). Altogether, TMEM43 emerges as a component that interfaces with mechanical, metabolic, and inflammatory signaling, largely by virtue of its role in anchoring multi-protein complexes that regulate gene expression in response to stress or stimuli.

Clinical Significance and Disease Associations

Arrhythmogenic Cardiomyopathy (ARVC5)

The most prominent disease tied to TMEM43 is Arrhythmogenic Right Ventricular Cardiomyopathy type 5 (ARVC5), an inherited heart muscle disorder. A missense mutation in TMEM43, p.S358L, was identified as the cause of ARVC5 in a large Newfoundland kindred (pmc.ncbi.nlm.nih.gov). ARVC5 is a fully penetrant, lethal arrhythmic disorder, meaning virtually all mutation carriers develop disease and many suffer life-threatening arrhythmias (pmc.ncbi.nlm.nih.gov). Clinically, TMEM43-related ARVC often presents with ventricular arrhythmias in young adulthood and progresses to ventricular dysfunction with fibro-fatty replacement of myocardium (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In the original family studies, male carriers of TMEM43-S358L had a particularly poor prognosis – approximately 48% of affected men died suddenly by middle age, whereas women carriers showed later onset and longer survival (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This sex-influenced severity is a notable feature of ARVC5. Mechanistically, the S358L mutation in TMEM43 has multiple effects on cardiac cells: it causes mislocalization of TMEM43 protein, disrupts intercalated disc integrity, and triggers pro-fibrotic and pro-apoptotic signaling cascades (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Mutant hearts show hallmark ARVC changes – myocardial cell loss with fibrous and fatty infiltrates, especially in the right ventricle’s “triangle of dysplasia” region (pmc.ncbi.nlm.nih.gov).

At the molecular level, TMEM43-S358L leads to a cascade of signal transduction changes that drive disease. Studies in knock-in mice carrying the human S358L mutation revealed activation of TGF-β and NF-κB signaling, known promoters of fibrosis and inflammation, in mutant hearts (pmc.ncbi.nlm.nih.gov). There is also a disruption of Wnt/β-catenin signaling: as mentioned, plakoglobin relocates to the nucleus in mutant cardiomyocytes, effectively dampening β-catenin’s transcriptional activity and promoting an adipogenic gene program (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In line with this, genes involved in adipogenesis (like PPARγ targets) become upregulated, and a switch toward fat metabolism is observed in the heart (pmc.ncbi.nlm.nih.gov). TMEM43 has been identified as one of the genes upregulated by PPARγ in cardiac tissue, suggesting that the mutant protein (or its downstream effects) might feed into a feed-forward loop of fat accumulation in myocardium (pmc.ncbi.nlm.nih.gov). Additionally, the mutant S358L protein itself appears unstable; studies noted its overall expression level is reduced in heterozygous carriers, possibly due to protein misfolding and degradation (pmc.ncbi.nlm.nih.gov). This reduction may phenocopy a partial loss-of-function, where cells lack sufficient TMEM43 at both the nuclear envelope and cell junctions. Indeed, cardiomyocytes harboring S358L show ultrastructural abnormalities: electron microscopy documented disarray of desmosomes and gap junctions, and nuclei that were abnormally shaped or stiff (pmc.ncbi.nlm.nih.gov). Cell mechanical testing indicated the S358L mutation increases nuclear stiffness, consistent with a perturbation in nucleo-cytoskeletal connections (pmc.ncbi.nlm.nih.gov). All these changes – weakened cell adhesion, altered signaling, and mechanical stress – synergize to cause cardiomyocyte death and fibrofatty replacement, manifesting as ARVC.

From a clinical perspective, the discovery of TMEM43 mutations in ARVC has practical implications. Genetic testing now includes TMEM43 in panels for arrhythmogenic cardiomyopathy, allowing at-risk family members to be identified early (pmc.ncbi.nlm.nih.gov). Because male sex and intense exercise exacerbate ARVC5, carriers (especially men) are advised to limit vigorous physical activity to reduce arrhythmia risk (pmc.ncbi.nlm.nih.gov). Some centers have even suggested implantable defibrillators at a relatively young age for S358L carriers, given the high incidence of sudden death (pmc.ncbi.nlm.nih.gov). There is ongoing research into therapies that might target the pathways activated by TMEM43 mutations – for example, NF-κB or TGF-β inhibitors to curb fibrosis, or Wnt modulators to correct the adipogenic switch (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). While no mutation-specific therapy exists yet, the mechanistic insights gained from TMEM43 studies (such as its influence on PPARγ and Wnt signaling) are guiding new approaches to ARVC treatment.

Emery–Dreifuss Muscular Dystrophy (EDMD) and Related Myopathies

Variants in TMEM43 have also been implicated in Emery–Dreifuss muscular dystrophy (EDMD)-like disease. EDMD is typically caused by mutations in emerin (EMD gene) or lamin A/C (LMNA), leading to muscle wasting, early joint contractures, and cardiac conduction defects. However, Liang et al. (2011) reported TMEM43 mutations (e.g. p.E85K and p.I91V) in patients with EDMD-type muscular dystrophy (pmc.ncbi.nlm.nih.gov). These individuals had progressive skeletal muscle weakness and contractures similar to EDMD, despite having normal emerin and lamin sequences (pmc.ncbi.nlm.nih.gov). The TMEM43 mutations in EDMD patients likely disrupt the same nuclear envelope network that emerin and lamins normally support. Muscle biopsies from TMEM43-mutant patients showed irregularly shaped nuclei, but immunostaining indicated emerin and other nuclear membrane proteins were still present (pmc.ncbi.nlm.nih.gov). This suggests TMEM43 mutations may cause a functional loss of emerin/lamin organization rather than complete absence. Indeed, researchers proposed that TMEM43 dysfunction leads to emerin mislocalization or degradation over time, weakening the LINC complex and nuclear-cytoskeletal connections in muscle (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The result is nuclear architectural defects and impaired mechanotransduction in muscle fibers, which can trigger muscle fiber damage and dystrophy. In support of this mechanism, experimental knockdown of TMEM43 in muscle cells causes loss of emerin from the nuclear membrane and abnormal nuclear morphology, recapitulating features of EDMD (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Thus, TMEM43 joins emerin and lamin A/C as a critical component of the nuclear envelope whose disruption can lead to EDMD. Clinically, TMEM43-linked EDMD is rare; it has been designated “EDMD7” in the literature to distinguish it from the X-linked (emerin) and autosomal (lamin A/C) forms (www.ncbi.nlm.nih.gov). Patients with TMEM43 mutations may have milder cardiac involvement than typical EDMD – for example, normal early echocardiograms with possible arrhythmias later in life (pmc.ncbi.nlm.nih.gov). However, they still benefit from monitoring for cardiomyopathy and from interventions like pacemakers if conduction block develops, similar to classic EDMD management.

Auditory Neuropathy and Hearing Loss

Another emerging role for TMEM43 is in the auditory system. Autosomal dominant auditory neuropathy spectrum disorder (ANSD) has been linked to a nonsense variant in TMEM43 (p.Arg372Ter) in two unrelated families (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Patients with this condition experience progressive hearing loss characterized by inability to understand speech despite the inner ear’s hair cells remaining functional (a disconnect between ear and auditory nerve) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Genetic analysis mapped the disorder to chromosome 3p25 and pinpointed the TMEM43 variant as causative (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Functional studies in mice carrying the Arg372Ter mutation provided insight into how TMEM43 supports hearing: the mutation led to degeneration of cochlear supporting cells and disruption of their gap junction coupling (pmc.ncbi.nlm.nih.gov). Normally, cochlear glial-like supporting cells are coupled by connexin gap junctions (Cx26 and Cx30) that allow dispersal of K^+ ions and metabolites. TMEM43 was found to interact with Cx26 and Cx30, and the mutant TMEM43 could not support the gap junction function, resulting in impaired ionic currents in the supporting cell network (pmc.ncbi.nlm.nih.gov). Essentially, loss of TMEM43 uncouples the supporting cells, hindering the inner ear’s ability to recycle ions after sound stimulation, which in turn compromises the firing of the auditory nerve. Importantly, this discovery had a real-world application: because the sensory hair cells were intact despite the neural dysfunction, patients were treated with cochlear implants, which bypass the defective neural coupling. After implantation, individuals with the TMEM43 mutation showed restored speech discrimination ability (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov) – a striking example of precision medicine guided by the molecular understanding of TMEM43’s role. Beyond gap junctions, as noted earlier, TMEM43 in the cochlea may also interact with ion channels like KCNK3 (TASK-1), indicating it might broadly influence the ion homeostasis in the inner ear’s supporting cell microenvironment (pmc.ncbi.nlm.nih.gov). TMEM43’s involvement in ANSD highlights its importance in cell–cell communication, extending its functional repertoire from muscle and heart into the nervous system.

Other Associations (Cancer and Beyond)

Studies have hinted at connections between TMEM43 and cancer, though this area is still being explored. Some analyses have found that certain TMEM43 mutations or expression patterns correlate with cancer outcomes. For instance, TMEM43 gene variations were noted to have a negative association with tumor progression and cell survival in some cancers (pmc.ncbi.nlm.nih.gov). This suggests that loss-of-function TMEM43 mutations might impede cancer cell growth (potentially because the cells lose structural integrity or NF-κB signaling support). Paradoxically, other experiments indicate that high TMEM43 expression can promote oncogenic behaviors, as described earlier with NF-κB activation and PRPF3 stabilization driving cancer cell proliferation (pmc.ncbi.nlm.nih.gov). One hypothesis to reconcile this is that TMEM43’s impact on cancer may be tissue-specific or context-dependent: in some cells, TMEM43-mediated mechanotransduction is required for tumor invasion (for example, cancer cells might exploit nuclear-cytoskeletal connections to migrate and endure physical stresses), whereas in other contexts, TMEM43-triggered pathways like NF-κB might induce senescence or immune responses that actually limit tumor growth. Large-scale data are needed to clarify TMEM43’s role in malignancy.

Outside of disease, TMEM43 has become of interest in cell biology as a protein that links multiple systems. Some experts have called TMEM43/LUMA a “unifying finding for cell biology and cardiology,” since it connects fundamental cellular structures (junctions and nuclei) with the pathology of heart disease (pubmed.ncbi.nlm.nih.gov). Its discovery at intercalated discs has prompted a re-thinking of how nuclear proteins might also function at the cell surface to maintain tissue integrity (pubmed.ncbi.nlm.nih.gov). In the heart, TMEM43 sits at the intersection of mechanical and electrical syncytia – reinforcing desmosomes while also influencing gene expression – a combination crucial for preventing arrhythmia. As such, TMEM43 exemplifies the concept of the “nexus” protein that integrates structural scaffolds with signaling pathways. Ongoing research is investigating TMEM43 in other conditions, such as its potential role in cardiometabolic disorders (given the link to PPARγ and lipid handling) (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). There is also interest in whether TMEM43 variants contribute to idiopathic cardiac fibrosis or heart failure in the general population, beyond the rare ARVC5 mutation carriers (pubmed.ncbi.nlm.nih.gov).

Summary

TMEM43 (LUMA) is a membrane protein that plays a pivotal role in maintaining cell structure and communication. Anchored in both the nuclear envelope and in cell–cell junctions, TMEM43 provides a physical and functional link between the nucleus and the plasma membrane. It helps stabilize the nuclear architecture by tethering lamins and emerin at the inner membrane (pmc.ncbi.nlm.nih.gov), and it fortifies intercellular junctions in tissues subject to mechanical stress (pubmed.ncbi.nlm.nih.gov). Through these roles, TMEM43 is a key mediator of mechanotransduction, ensuring that mechanical forces are relayed to the nucleus to influence gene activity (pmc.ncbi.nlm.nih.gov). Its influence extends to various signaling pathways – notably Wnt/β-catenin, PPARγ, and NF-κB – which become dysregulated when TMEM43 is mutated (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The critical importance of TMEM43 is highlighted by the severe diseases associated with its mutations: a lethal arrhythmogenic cardiomyopathy (ARVC5) characterized by sudden cardiac death and fatty heart degeneration (pmc.ncbi.nlm.nih.gov), a form of muscular dystrophy (EDMD) that undermines nuclear stability in muscle cells (pmc.ncbi.nlm.nih.gov), and an auditory neuropathy that uncouples inner-ear support cells leading to hearing loss (pmc.ncbi.nlm.nih.gov). In each case, the pathology can be traced back to the loss of TMEM43’s structural support and the resultant cascade of abnormal signaling and cell stress.

Experts continue to investigate TMEM43 to fully map its interactome and regulation. As a protein with “broad cellular functions”, spanning muscle, heart, ear, and possibly cancer contexts (pubmed.ncbi.nlm.nih.gov), TMEM43 represents a nexus between cell architecture and function. Understanding TMEM43’s role offers valuable insight into how cells convert physical cues into biological responses, and provides avenues for therapeutic intervention – from gene therapy for inherited cardiomyopathy to targeted cochlear implants for hearing loss. As of 2024, TMEM43 stands as a prime example of how a single membrane protein can influence diverse physiological processes through its integrative structural role, and research into its mechanism remains an active and fruitful field.

References:

1. Bengtsson, L. & Otto, H. (2008). LUMA interacts with emerin and influences its distribution at the inner nuclear membrane. J. Cell Sci. 121(4): 536–548. DOI: 10.1242/jcs.019281 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

2. Dreger, M. et al. (2001). Nuclear envelope proteomics: novel integral membrane proteins of the inner nuclear membrane. Proc. Natl. Acad. Sci. USA 98(21): 11943–11948. DOI: 10.1073/pnas.211201898 (pmc.ncbi.nlm.nih.gov).

3. Franke, W.W. et al. (2014). Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology. Cell Tissue Res. 357(1): 159–172. DOI: 10.1007/s00441-014-1865-1 (pubmed.ncbi.nlm.nih.gov).

4. Merner, N.D. et al. (2008). Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am. J. Hum. Genet. 82(4): 809–821. DOI: 10.1016/j.ajhg.2008.01.010 (pmc.ncbi.nlm.nih.gov).

5. Christensen, A.H. et al. (2011). Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy. Clin. Genet. 80(3): 256–264. DOI: 10.1111/j.1399-0004.2011.01623.x (pmc.ncbi.nlm.nih.gov).

6. Liang, W.C. et al. (2011). TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy. Ann. Neurol. 69(6): 1005–1013. DOI: 10.1002/ana.22338 (pmc.ncbi.nlm.nih.gov).

7. Zhao, Y. et al. (2021). A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder. Proc. Natl. Acad. Sci. U.S.A. 118(22): e2019681118. DOI: 10.1073/pnas.2019681118 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

8. Orgil, B.-O. et al. (2023). The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model. Am. J. Physiol. Heart Circ. Physiol. 324(6): H866–H880. DOI: 10.1152/ajpheart.00712.2022 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

9. Orgil, B.-O. et al. (2025). Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases. Int. J. Mol. Sci. 26(14): 6856. DOI: 10.3390/ijms26146856 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

10. Hodgkinson, K.A. et al. (2013). The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. Clin. Genet. 83(4): 321–331. DOI: 10.1111/cge.12093 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Citations

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4. AnnotationURLCitation(end_index=1330, start_index=1196, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=More%20recent%20reports%20have%20demonstrated,DSP')
5. AnnotationURLCitation(end_index=1662, start_index=1495, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=The%20transmembrane%20protein%2043%20,observed%20in%20female%20mutation%20carriers')
6. AnnotationURLCitation(end_index=2092, start_index=1965, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=In%20a%20series%20of%20recent,In%20CJs%2C%20LUMA')
7. AnnotationURLCitation(end_index=2611, start_index=2459, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=45%20kDa%2C%20expressed%20in%20the,Genetic%20mutations%20and%20gene')
8. AnnotationURLCitation(end_index=2767, start_index=2612, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=ER%20membranes%20in%20many%20cell,Expression%20of%20TMEM43%20is%20also')
9. AnnotationURLCitation(end_index=3019, start_index=2866, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=Transmembrane%20protein%2043%20,that%20are%20permeable%20to%20sodium')
10. AnnotationURLCitation(end_index=3180, start_index=3020, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=TMEM43%20is%20an%20integral%20membrane,Expression%20of%20TMEM43%20is%20also')
11. AnnotationURLCitation(end_index=3729, start_index=3568, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=location%20and%20organization,interactions%20to%20the%20intercalated%20disks')
12. AnnotationURLCitation(end_index=4073, start_index=3912, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=location%20and%20organization,interactions%20to%20the%20intercalated%20disks')
13. AnnotationURLCitation(end_index=4423, start_index=4262, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=location%20and%20organization,interactions%20to%20the%20intercalated%20disks')
14. AnnotationURLCitation(end_index=4693, start_index=4532, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=location%20and%20organization,interactions%20to%20the%20intercalated%20disks')
15. AnnotationURLCitation(end_index=4955, start_index=4853, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=,Google%20Scholar')
16. AnnotationURLCitation(end_index=5452, start_index=5294, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=progression%20of%20various%20cancers%20in,to%20play%20a%20critical%20role')
17. AnnotationURLCitation(end_index=5968, start_index=5807, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=we%20have%20discovered%20that%2C%20in,to%20reconsiderations%20of%20the%20molecular')
18. AnnotationURLCitation(end_index=6319, start_index=6158, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=we%20have%20discovered%20that%2C%20in,to%20reconsiderations%20of%20the%20molecular')
19. AnnotationURLCitation(end_index=6925, start_index=6763, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=of%20muscle%20cells,%E2%80%9Cdomino%20effect%E2%80%9D%20disruption%20of%20the')
20. AnnotationURLCitation(end_index=7180, start_index=7019, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=we%20have%20discovered%20that%2C%20in,to%20reconsiderations%20of%20the%20molecular')
21. AnnotationURLCitation(end_index=7615, start_index=7481, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=More%20recent%20reports%20have%20demonstrated,DSP')
22. AnnotationURLCitation(end_index=8058, start_index=7916, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=Transmembrane%20protein%2043%20,S358L%20mutation%20causes')
23. AnnotationURLCitation(end_index=8232, start_index=8059, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=Schema%20of%20the%20nuclear%20envelope,membrane%3B%20ONM%2C%20outer%20nuclear%20membrane')
24. AnnotationURLCitation(end_index=8787, start_index=8650, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=cellular%20processes%20,is%20thought%20to%20play%20a')
25. AnnotationURLCitation(end_index=9109, start_index=8955, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=cytoskeleton%20are%20essential%20for%20a,is%20thought%20to%20play%20a')
26. AnnotationURLCitation(end_index=9283, start_index=9110, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=Schema%20of%20the%20nuclear%20envelope,membrane%3B%20ONM%2C%20outer%20nuclear%20membrane')
27. AnnotationURLCitation(end_index=9481, start_index=9364, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=location%20and%20organization,33')
28. AnnotationURLCitation(end_index=9839, start_index=9660, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=role%20in%20mechanosensation%20by%20transmitting,Emerins%20are%20ubiquitously%20expressed%20in')
29. AnnotationURLCitation(end_index=10139, start_index=10002, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=cellular%20processes%20,is%20thought%20to%20play%20a')
30. AnnotationURLCitation(end_index=10481, start_index=10302, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=role%20in%20mechanosensation%20by%20transmitting,Emerins%20are%20ubiquitously%20expressed%20in')
31. AnnotationURLCitation(end_index=10946, start_index=10765, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L680%20interacted%20with,calcineurin%20splice%20variant%2C%20A%CE%B21%2C%20resulted')
32. AnnotationURLCitation(end_index=11326, start_index=11145, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L680%20interacted%20with,calcineurin%20splice%20variant%2C%20A%CE%B21%2C%20resulted')
33. AnnotationURLCitation(end_index=11607, start_index=11426, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L680%20interacted%20with,calcineurin%20splice%20variant%2C%20A%CE%B21%2C%20resulted')
34. AnnotationURLCitation(end_index=12644, start_index=12483, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=we%20have%20discovered%20that%2C%20in,to%20reconsiderations%20of%20the%20molecular')
35. AnnotationURLCitation(end_index=13411, start_index=13216, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=analysis%20found%20significantly%20differentially%20expressed,and%20PPARG%20signaling%20thereby%20contributing')
36. AnnotationURLCitation(end_index=13830, start_index=13641, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=diminished%20PPARG%20activities%20and%20significantly,suggest%20that%20cardiometabolic%20assessment%20in')
37. AnnotationURLCitation(end_index=14504, start_index=14369, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=p,subjects%2C%20and%20speech%20discrimination%20was')
38. AnnotationURLCitation(end_index=14937, start_index=14802, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=p,subjects%2C%20and%20speech%20discrimination%20was')
39. AnnotationURLCitation(end_index=15243, start_index=15108, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=p,subjects%2C%20and%20speech%20discrimination%20was')
40. AnnotationURLCitation(end_index=15562, start_index=15418, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=2014%3B357%3A159%E2%80%93172.%20doi%3A%2010.1007%2Fs00441,M')
41. AnnotationURLCitation(end_index=16291, start_index=16159, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=critical%20role%20in%20emerin%20localization,47')
42. AnnotationURLCitation(end_index=16611, start_index=16477, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=tissues%20and%20predominately%20localized%20to,47')
43. AnnotationURLCitation(end_index=17107, start_index=16912, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=analysis%20found%20significantly%20differentially%20expressed,and%20PPARG%20signaling%20thereby%20contributing')
44. AnnotationURLCitation(end_index=17560, start_index=17371, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=diminished%20PPARG%20activities%20and%20significantly,suggest%20that%20cardiometabolic%20assessment%20in')
45. AnnotationURLCitation(end_index=18094, start_index=17974, title='TMEM43 transmembrane protein 43 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/79188#:~:text=This%20gene%20belongs%20to%20the,provided%20by')
46. AnnotationURLCitation(end_index=18357, start_index=18215, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=preferential%20loss%20of%20compact%20myocardium,146%2C126')
47. AnnotationURLCitation(end_index=18734, start_index=18583, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=preferential%20loss%20of%20compact%20myocardium,127%5D%2C%20sodium')
48. AnnotationURLCitation(end_index=19164, start_index=18967, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=analysis%20found%20significantly%20differentially%20expressed,suggest%20that%20cardiometabolic%20assessment%20in')
49. AnnotationURLCitation(end_index=19658, start_index=19518, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=mutation%20,higher%20fat%20displacement%20of%20myocytes')
50. AnnotationURLCitation(end_index=20127, start_index=20003, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L78%20TMEM43%20was,12%2C14')
51. AnnotationURLCitation(end_index=20435, start_index=20311, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L78%20TMEM43%20was,12%2C14')
52. AnnotationURLCitation(end_index=20981, start_index=20881, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=senescence,MRNA')
53. AnnotationURLCitation(end_index=21378, start_index=21221, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=The%20ELGAN%20cohort%20study%20of,study%20defined%20a%20potential%20link')
54. AnnotationURLCitation(end_index=22091, start_index=21989, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=,Google%20Scholar')
55. AnnotationURLCitation(end_index=22415, start_index=22254, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=The%20transmembrane%20protein%2043%20,Serial%20echocardiography%2C%20surface')
56. AnnotationURLCitation(end_index=22763, start_index=22601, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=SCD%20develop%20fibrosis%20with%20fatty,survival%20with%20the%20median%20life')
57. AnnotationURLCitation(end_index=22923, start_index=22764, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=pathogenic%20variants%20,carried%20on%20all%20recombinant%20arrhythmogenic')
58. AnnotationURLCitation(end_index=23282, start_index=23152, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=,lethal%20arrhythmic%20disorder%20caused%20by')
59. AnnotationURLCitation(end_index=23445, start_index=23283, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=SCD%20develop%20fibrosis%20with%20fatty,survival%20with%20the%20median%20life')
60. AnnotationURLCitation(end_index=23885, start_index=23742, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=displayed%20intolerance%20to%20acute%20stress,We%20defined')
61. AnnotationURLCitation(end_index=24021, start_index=23886, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L472%20and%20fibrosis,109%2C110%2C111')
62. AnnotationURLCitation(end_index=24349, start_index=24190, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=stability%2C%20and%20mechanical%20function%20of,fatty%20replacement%20with')
63. AnnotationURLCitation(end_index=24776, start_index=24641, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L472%20and%20fibrosis,109%2C110%2C111')
64. AnnotationURLCitation(end_index=25205, start_index=25010, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=analysis%20found%20significantly%20differentially%20expressed,and%20PPARG%20signaling%20thereby%20contributing')
65. AnnotationURLCitation(end_index=25353, start_index=25206, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=and%20fibrosis%20through%20various%20signaling,109%2C110%2C111')
66. AnnotationURLCitation(end_index=25661, start_index=25510, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=preferential%20loss%20of%20compact%20myocardium,127%5D%2C%20sodium')
67. AnnotationURLCitation(end_index=26038, start_index=25887, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=preferential%20loss%20of%20compact%20myocardium,127%5D%2C%20sodium')
68. AnnotationURLCitation(end_index=26430, start_index=26235, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=analysis%20found%20significantly%20differentially%20expressed,and%20PPARG%20signaling%20thereby%20contributing')
69. AnnotationURLCitation(end_index=26939, start_index=26773, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=arrhythmogenic%20right%20ventricular%20cardiomyopathy,0004.2011.01623.x.%20%5BDOI')
70. AnnotationURLCitation(end_index=27206, start_index=27093, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=,2015%3B36%3A872%E2%80%93881')
71. AnnotationURLCitation(end_index=27727, start_index=27625, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=,Google%20Scholar')
72. AnnotationURLCitation(end_index=28046, start_index=27885, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=The%20transmembrane%20protein%2043%20,Serial%20echocardiography%2C%20surface')
73. AnnotationURLCitation(end_index=28325, start_index=28195, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=,lethal%20arrhythmic%20disorder%20caused%20by')
74. AnnotationURLCitation(end_index=28686, start_index=28551, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L472%20and%20fibrosis,109%2C110%2C111')
75. AnnotationURLCitation(end_index=28820, start_index=28687, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=mutation%20,ACM%20patients%20with%20high%20serum')
76. AnnotationURLCitation(end_index=29635, start_index=29495, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=localization%2C%20resulting%20in%20impaired%20cell,This')
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78. AnnotationURLCitation(end_index=30336, start_index=30176, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L894%20dystroglycan%2C%20beta,It%20was%20proposed%20that%20the')
79. AnnotationURLCitation(end_index=30831, start_index=30647, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=in%20TMEM43%20resulting%20in%20emerin,dystrophy%2C%20joint%20contractures%2C%20and%20cardiomyopathy')
80. AnnotationURLCitation(end_index=30995, start_index=30832, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=LINC%20complex%20interactions%20with%20nuclear,related%20myopathy%20phenotypes')
81. AnnotationURLCitation(end_index=31525, start_index=31341, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=in%20TMEM43%20resulting%20in%20emerin,dystrophy%2C%20joint%20contractures%2C%20and%20cardiomyopathy')
82. AnnotationURLCitation(end_index=31677, start_index=31526, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L905%20LINC%20complex,related%20myopathy%20phenotypes')
83. AnnotationURLCitation(end_index=32136, start_index=31972, title='TMEM43 transmembrane protein 43 [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/79188#:~:text=Also%20known%20as%20LUMA%3B%20ARVC5%3B,is%20characterized%20by%20ventricular%20tachycardia')
84. AnnotationURLCitation(end_index=32467, start_index=32307, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L894%20dystroglycan%2C%20beta,It%20was%20proposed%20that%20the')
85. AnnotationURLCitation(end_index=33075, start_index=32897, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=Auditory%20neuropathy%20spectrum%20disorder%20,passive%20conductance%20current%20in%20cochlear')
86. AnnotationURLCitation(end_index=33255, start_index=33076, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=Genes%20that%20are%20primarily%20expressed,Mechanistically%2C%20TMEM43%20interacts%20with%20the')
87. AnnotationURLCitation(end_index=33568, start_index=33472, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=Significance')
88. AnnotationURLCitation(end_index=33661, start_index=33569, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=Abstract')
89. AnnotationURLCitation(end_index=33912, start_index=33766, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=discrimination,and%20their%20speech%20discrimination%20ability')
90. AnnotationURLCitation(end_index=34092, start_index=33913, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=Genes%20that%20are%20primarily%20expressed,Mechanistically%2C%20TMEM43%20interacts%20with%20the')
91. AnnotationURLCitation(end_index=34447, start_index=34312, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=p,subjects%2C%20and%20speech%20discrimination%20was')
92. AnnotationURLCitation(end_index=34923, start_index=34788, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=p,subjects%2C%20and%20speech%20discrimination%20was')
93. AnnotationURLCitation(end_index=35586, start_index=35450, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=p,speech%20discrimination%20ability%20was%20restored')
94. AnnotationURLCitation(end_index=35730, start_index=35587, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=connexin,speech%20discrimination%20ability%20was%20restored')
95. AnnotationURLCitation(end_index=36203, start_index=36059, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=2014%3B357%3A159%E2%80%93172.%20doi%3A%2010.1007%2Fs00441,M')
96. AnnotationURLCitation(end_index=36964, start_index=36775, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=arrhythmogenic%20right%20ventricular%20cardiomyopathy%20type,studies%20that%20describe%20the%20molecular')
97. AnnotationURLCitation(end_index=37469, start_index=37345, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L78%20TMEM43%20was,12%2C14')
98. AnnotationURLCitation(end_index=38461, start_index=38305, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=and%20is%20also%20located%20in,of%20mutations%20of%20cardiomyocyte%20junction')
99. AnnotationURLCitation(end_index=38793, start_index=38619, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=conditions%2C%20similar%20CJ%20localizations%20have,may%20be%20involved%20in%20cardiomyopathies')
100. AnnotationURLCitation(end_index=39431, start_index=39286, title='Systems genetics analysis defines importance of TMEM43/ LUMA for cardiac- and metabolic-related pathways - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/34766515/#:~:text=Broad%20cellular%20functions%20and%20diseases,The%20results%20were')
101. AnnotationURLCitation(end_index=39604, start_index=39432, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=gender%20and%20vigorous%20exercise%20independently,Electron%20microscopy%2C%20histology')
102. AnnotationURLCitation(end_index=39927, start_index=39782, title='Systems genetics analysis defines importance of TMEM43/ LUMA for cardiac- and metabolic-related pathways - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/34766515/#:~:text=Broad%20cellular%20functions%20and%20diseases,The%20results%20were')
103. AnnotationURLCitation(end_index=40475, start_index=40314, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=location%20and%20organization,interactions%20to%20the%20intercalated%20disks')
104. AnnotationURLCitation(end_index=40719, start_index=40558, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=we%20have%20discovered%20that%2C%20in,to%20reconsiderations%20of%20the%20molecular')
105. AnnotationURLCitation(end_index=41018, start_index=40881, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=cellular%20processes%20,is%20thought%20to%20play%20a')
106. AnnotationURLCitation(end_index=41354, start_index=41165, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=diminished%20PPARG%20activities%20and%20significantly,suggest%20that%20cardiometabolic%20assessment%20in')
107. AnnotationURLCitation(end_index=41506, start_index=41355, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=preferential%20loss%20of%20compact%20myocardium,127%5D%2C%20sodium')
108. AnnotationURLCitation(end_index=41642, start_index=41507, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L472%20and%20fibrosis,109%2C110%2C111')
109. AnnotationURLCitation(end_index=42022, start_index=41861, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=The%20transmembrane%20protein%2043%20,Serial%20echocardiography%2C%20surface')
110. AnnotationURLCitation(end_index=42294, start_index=42110, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=in%20TMEM43%20resulting%20in%20emerin,dystrophy%2C%20joint%20contractures%2C%20and%20cardiomyopathy')
111. AnnotationURLCitation(end_index=42521, start_index=42386, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=p,subjects%2C%20and%20speech%20discrimination%20was')
112. AnnotationURLCitation(end_index=43048, start_index=42872, title='Systems genetics analysis defines importance of TMEM43/ LUMA for cardiac- and metabolic-related pathways - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/34766515/#:~:text=Broad%20cellular%20functions%20and%20diseases,through%20genetic%20regulation%2C%20gene%20pathways')
113. AnnotationURLCitation(end_index=43983, start_index=43822, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=location%20and%20organization,interactions%20to%20the%20intercalated%20disks')
114. AnnotationURLCitation(end_index=44086, start_index=43984, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=,Google%20Scholar')
115. AnnotationURLCitation(end_index=44457, start_index=44296, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=location%20and%20organization,interactions%20to%20the%20intercalated%20disks')
116. AnnotationURLCitation(end_index=44926, start_index=44765, title='Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/24770932/#:~:text=we%20have%20discovered%20that%2C%20in,to%20reconsiderations%20of%20the%20molecular')
117. AnnotationURLCitation(end_index=45351, start_index=45190, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=The%20transmembrane%20protein%2043%20,Serial%20echocardiography%2C%20surface')
118. AnnotationURLCitation(end_index=45723, start_index=45589, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=More%20recent%20reports%20have%20demonstrated,DSP')
119. AnnotationURLCitation(end_index=46031, start_index=45891, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=localization%2C%20resulting%20in%20impaired%20cell,This')
120. AnnotationURLCitation(end_index=46422, start_index=46287, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=p,subjects%2C%20and%20speech%20discrimination%20was')
121. AnnotationURLCitation(end_index=46601, start_index=46423, title='A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8179140/#:~:text=Auditory%20neuropathy%20spectrum%20disorder%20,passive%20conductance%20current%20in%20cochlear')
122. AnnotationURLCitation(end_index=46996, start_index=46846, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=ventricular%20,suggest%20that%20cardiometabolic%20assessment%20in')
123. AnnotationURLCitation(end_index=47158, start_index=46997, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=The%20transmembrane%20protein%2043%20,Serial%20echocardiography%2C%20surface')
124. AnnotationURLCitation(end_index=47535, start_index=47386, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=Transmembrane%20protein%2043%20,5%20and%20is%20associated%20with')
125. AnnotationURLCitation(end_index=47671, start_index=47536, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=match%20at%20L472%20and%20fibrosis,109%2C110%2C111')
126. AnnotationURLCitation(end_index=47992, start_index=47903, title='The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10190833/#:~:text=,doi')
127. AnnotationURLCitation(end_index=48155, start_index=47993, title='Transmembrane Protein 43: Molecular and Pathogenetic Implications in Arrhythmogenic Cardiomyopathy and Various Other Diseases - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC12295021/#:~:text=SCD%20develop%20fibrosis%20with%20fatty,survival%20with%20the%20median%20life')