KCNRG (Potassium Channel Regulatory Protein) – Gene Function and Current Insights OpenAI o3-deep-research-2025-06-26 105 citations 2025-12-27T16:45:12.772142

KCNRG (Potassium Channel Regulatory Protein) – Gene Function and Current Insights

Gene Identity and Structure

The KCNRG gene (HGNC:18893) encodes a Potassium Channel Regulatory Protein, also known as CLLD4 (Chronic Lymphocytic Leukemia Deleted gene 4) (www.genecards.org) (www.ncbi.nlm.nih.gov). It is a human protein-coding gene located on chromosome 13q14.3, overlapping the TRIM13 (RFP2) gene on the same strand (www.ncbi.nlm.nih.gov). KCNRG gives rise to multiple mRNA transcripts due to alternative splicing, encoding two main isoforms of 229 and 272 amino acids (www.sciencedirect.com). These isoforms share an identical N-terminus and differ only in their C-terminal region (www.sciencedirect.com). Notably, the KCNRG protein sequence contains a BTB/POZ domain (Broad-Complex, Tramtrack, Bric-à-Brac) homologous to the tetramerization (T1) domain of voltage-gated potassium (K⁺) channels (www.sciencedirect.com). This BTB/POZ domain is a well-known protein-protein interaction module that mediates oligomerization; in Kv channels it enables subunits to assemble into tetramers (www.sciencedirect.com). The presence of this domain in KCNRG immediately suggested it might interface with K⁺ channel subunits (www.sciencedirect.com) (www.sciencedirect.com). Consistent with its lack of any transmembrane segment, KCNRG is a soluble, intracellular protein (www.sciencedirect.com), predicted to reside in the cytoplasm and/or on cytosolic faces of membranes where it can interact with channel proteins.

Verification: The KCNRG symbol is unambiguous for the human gene described above. It should not be confused with similarly named loci in other species. All literature and data cited herein refer to human KCNRG (UniProt Q8N5I3), which contains the BTB/T1 domain and is distinct from other K⁺ channel subunits. The UniProt description “Potassium channel regulatory protein (CLLD4)” matches this gene (www.genecards.org), and the genomic context (13q14.3 in Homo sapiens) is confirmed by multiple sources (www.ncbi.nlm.nih.gov).

Expression and Localization

KCNRG is expressed ubiquitously at the mRNA level, with particularly high expression reported in testis and bone marrow among human tissues (www.ncbi.nlm.nih.gov). Early characterization detected KCNRG transcripts in all normal tissues examined, as well as some tumor cell lines (www.sciencedirect.com) (www.sciencedirect.com). Protein-level analysis has shown KCNRG to be notably present in the lung: it is predominantly expressed in the epithelial cells of terminal bronchioles (pmc.ncbi.nlm.nih.gov). In fact, KCNRG was identified as a bronchial autoantigen – patients with autoimmune polyendocrine syndrome type 1 (APS-1) who develop autoimmune lung disease frequently produce autoantibodies against KCNRG (pmc.ncbi.nlm.nih.gov). This finding indicates KCNRG protein is accessible and immunologically relevant in the lung. Similarly, during acute inflammatory conditions like ARDS (acute respiratory distress syndrome) and sepsis, KCNRG emerges as a common autoantibody target, likely due to lung tissue damage releasing the protein (pmc.ncbi.nlm.nih.gov). Together, these observations underscore that KCNRG protein is expressed in pulmonary tissues and can localize to the bronchial epithelium in vivo (pmc.ncbi.nlm.nih.gov). Given that KCNRG lacks a membrane-spanning region, it is presumed to function on the cytosolic side of cellular membranes. The UniProt curation suggests KCNRG may tether certain K⁺ channels in intracellular compartments (endomembranes), effectively retaining a fraction of channels inside the cell (www.genecards.org). This is consistent with its diffuse cytosolic localization and binding capacity. No evidence points to nuclear localization or DNA/RNA-binding activity – its known interactions are protein-protein in nature (e.g. identical protein binding and likely binding to channel subunits) (www.genecards.org).

Mechanism: Regulation of Potassium Channels

KCNRG’s primary function is to suppress voltage-gated K⁺ channel activity in cells. This was first demonstrated by functional assays: when KCNRG is ectopically expressed in cells, it causes a significant reduction in K⁺ currents through voltage-gated channels (www.sciencedirect.com). For example, in human LNCaP prostate cells, whole-cell patch-clamp recordings showed that introducing KCNRG markedly decreased the K⁺ current density compared to control cells (www.sciencedirect.com). How does KCNRG achieve this inhibition? The current understanding is that KCNRG interferes with the normal assembly of K⁺ channel α-subunits. Voltage-gated K⁺ (Kv) channels are tetramers of pore-forming α-subunits, which rely on their N-terminal T1 domains to co-assemble into a functional channel complex. KCNRG, having a homologous T1 (BTB) domain, likely acts as a competitive binding partner for Kv channel subunits (www.sciencedirect.com) (www.sciencedirect.com). Experimental evidence and homology analysis support this model: KCNRG’s BTB domain shows strong sequence similarity to the Kv1 family T1 domain (e.g., PF02214) (www.sciencedirect.com), suggesting it can bind the same interfaces used by channel subunits during tetramerization. Researchers proposed that KCNRG protein can bind to K⁺ channel subunits via this domain, preventing proper tetramer formation and/or causing misassembly of the channel complex (www.sciencedirect.com). As a result, fewer functional channels reach the plasma membrane, leading to suppressed K⁺ flux. In line with this, hydrophilicity analyses confirm KCNRG is a cytosolic protein, not an ion channel itself, reinforcing that its effect is through channel binding rather than pore formation (www.sciencedirect.com).

The inhibitory impact of KCNRG appears to be selective for certain channel families – it is often described as regulating the Kv1 subfamily of K⁺ channels in particular (www.genecards.org). The UniProt/Swiss-Prot annotation suggests KCNRG may retain a fraction of Kv1 channels in the endoplasmic reticulum or Golgi, thereby reducing surface expression of these channels (www.genecards.org). This mechanism is analogous to having an “intracellular channel blocker” or a dominant-negative subunit. By curtailing K⁺ currents, KCNRG can influence the cell’s membrane potential and downstream signaling. K⁺ channel activity is known to facilitate cell proliferation in many contexts (www.sciencedirect.com). Kv channels (e.g., Kv1.3, EAG family) help set the resting potential and modulate calcium influx; heightened K⁺ conductance tends to promote cell-cycle progression in lymphocytes and other cells (www.sciencedirect.com) (www.sciencedirect.com). Conversely, blocking K⁺ channels can arrest cell division or induce apoptosis (www.sciencedirect.com). KCNRG essentially mimics the effect of K⁺ channel blockers: its expression in LNCaP prostate cancer cells was shown to reduce the mitotic rate (www.sciencedirect.com), and in hematopoietic cell lines it causes growth suppression and morphological changes (discussed below) (pmc.ncbi.nlm.nih.gov). Thus, the biochemical role of KCNRG – binding K⁺ channel subunits and dampening their activity – has direct consequences for cellular physiology, especially in contexts where K⁺ currents drive proliferation or activation.

Notably, KCNRG belongs to the KCTD (Potassium Channel Tetramerization Domain-containing) protein family, which comprises 25 members in humans (pmc.ncbi.nlm.nih.gov). Many KCTD proteins use their BTB domains to recruit Cullin-3 (CUL3), functioning as adaptors in ubiquitin E3 ligase complexes that target specific substrates for degradation (pmc.ncbi.nlm.nih.gov). However, KCNRG appears to be an exception within this family. A comprehensive 2024 structural analysis (using AlphaFold modeling and bioinformatics) found that KCNRG’s BTB domain does not stably bind CUL3, unlike most KCTDs (pmc.ncbi.nlm.nih.gov). In the study’s assays, KCNRG failed to form a complex with CUL3, whereas related BTB domains (e.g. from KCTD6 or KCTD11) bound readily (pmc.ncbi.nlm.nih.gov). This suggests KCNRG’s function is independent of the ubiquitin-proteasome pathway; instead of tagging channels for degradation, it likely works by the physical assembly blockade described above. KCNRG and KCTD6 form a small sub-cluster of KCTDs with differing CUL3 binding properties, where KCTD6 can bind CUL3 but KCNRG cannot (pmc.ncbi.nlm.nih.gov) (www.mdpi.com). Evolutionarily, KCNRG is considered a somewhat atypical KCTD, sharing the conserved BTB/T1 domain but otherwise divergent in sequence from other family members (pmc.ncbi.nlm.nih.gov). Its unique inability to recruit CUL3 and its specialized role in K⁺ channel regulation set it apart from ubiquitin-dependent KCTDs.

Biological Role and Pathways

KCNRG’s chief biological role is tied to its regulation of cell excitability and proliferation via K⁺ channel modulation. By suppressing K⁺ currents, KCNRG can alter the membrane potential of cells. In excitable cells (like neurons or muscle), reducing K⁺ channel activity would tend to depolarize the cell or limit repolarization, potentially affecting excitability. However, KCNRG expression is not prominently noted in brain or muscle; instead, it is found in tissues like immune organs, testis, and lung (www.ncbi.nlm.nih.gov). Its function may therefore be more relevant to non-excitable cells such as lymphocytes or epithelial cells, where Kv channels serve roles in signaling and volume regulation rather than firing action potentials. In lymphocytes, Kv1.3 channels are crucial for sustaining the calcium signals needed for activation and proliferation. The discovery of KCNRG in the deletion hotspot of chronic lymphocytic leukemia (CLL) drew immediate interest to its role in the immune system. CLL cells (malignant B-lymphocytes) and other immature lymphocytes show upregulated K⁺ channel activity compared to resting cells (www.sciencedirect.com). K⁺ efflux helps maintain a negative membrane potential, which is required for calcium entry through CRAC channels during activation. By suppressing Kv currents, KCNRG would impair this calcium signaling cascade, thereby inhibiting lymphocyte activation and proliferation. This mechanistic link underlies its proposed tumor-suppressive effect (see next section). Indeed, the normal function of KCNRG may be to act as a check on cell activation or growth in contexts like the immune system or testis, although this remains to be fully elucidated.

Apart from cell cycle regulation, KCNRG might intersect with specific signaling pathways indirectly. No dedicated metabolic or signaling pathway for KCNRG is established yet, but its effects feed into pathways controlled by membrane voltage and ion flux. For instance, reduced K⁺ efflux can lead to depolarization and reduced driving force for Ca²⁺ entry, which can dampen pathways like NF-κB or MAPK that require calcium signals in immune cells. A 2010 study of KCNRG in leukemia cells observed increased apoptosis and changes in cell morphology upon KCNRG overexpression (pmc.ncbi.nlm.nih.gov), suggesting it may activate apoptotic pathways when it shuts down K⁺ channel-mediated survival signals. Additionally, hinting at broader pathway involvement, the gene lies in a genomic region (13q14) where several tumor suppressors including MIR15A/MIR16-1 (microRNAs that downregulate BCL2) reside (pubmed.ncbi.nlm.nih.gov). There is evidence that genes in this locus, including KCNRG, are co-regulated and functionally linked in common pathways (possibly related to NF-κB regulation and apoptosis) (pubmed.ncbi.nlm.nih.gov). For example, one hypothesis is that loss of KCNRG and these microRNAs together disrupts cellular homeostasis to promote CLL (pubmed.ncbi.nlm.nih.gov).

It’s also worth noting KCNRG’s role in the context of the immune system and autoimmunity. The fact that KCNRG becomes a target of autoantibodies in APS-1 and sepsis/ARDS implies that the protein might be upregulated or particularly immunogenic in lung tissue during inflammation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). KCNRG’s pulmonary expression could relate to a defensive role: K⁺ channels are key in fluid secretion and ciliary beating in airways, so a regulator of K⁺ channels might influence mucociliary clearance or epithelial responses. These connections remain speculative, as direct studies on KCNRG in normal physiology (e.g. knockout mouse models or signaling assays) are not extensively documented in the literature.

KCNRG in Disease: Tumor Suppressor Function and Clinical Significance

Role in Cancer (CLL, Lymphomas, and Solid Tumors)

KCNRG was originally identified as a candidate tumor suppressor gene because of its location in the most frequent deletion in chronic lymphocytic leukemia. Over 50% of CLL patients have a deletion of chromosome 13q14.3 (pubmed.ncbi.nlm.nih.gov), which pointed to this region harboring critical growth-suppressing genes. Initial sequencing efforts did not find inactivating point mutations in obvious genes, so researchers searched the genomic sequence and discovered KCNRG as a new gene in this interval (www.sciencedirect.com). Early functional tests immediately supported a tumor suppressor role: KCNRG re-expression curbed cell proliferation in cancer cell lines. A 2003 study by Ishida et al. (FEBS Letters) reported that transfecting KCNRG into LNCaP prostate cancer cells not only reduced K⁺ currents but also slowed cell growth (www.sciencedirect.com). By 2010, more direct evidence emerged in blood cancer models: stable overexpression of KCNRG in leukemia and myeloma cell lines (HL-60, RPMI-8226, etc.) caused a suppression of growth and induced apoptosis (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Cells with ectopic KCNRG also showed changes in size/shape and a decrease in migratory capacity in vitro (pmc.ncbi.nlm.nih.gov). These phenotypes mirror the effects of K⁺ channel blockers on cancer cells, linking KCNRG’s molecular function to anti-proliferative outcomes.

Crucially, the loss of KCNRG in tumors correlates with disease presence and progression. In CLL, the 13q14 deletion (which encompasses KCNRG) is not only common but often the sole abnormality in early-stage disease, suggesting it confers a growth advantage when heterozygously lost. The remaining KCNRG allele in CLL typically shows reduced expression (haploinsufficiency) (pubmed.ncbi.nlm.nih.gov). In one study, primary lymphoma samples had significantly lower KCNRG mRNA levels than normal lymphocytes, especially the shorter isoform transcript (pubmed.ncbi.nlm.nih.gov). This downregulation beyond simple gene dosage hints at epigenetic silencing or microRNA-mediated suppression in the cancer cells (pubmed.ncbi.nlm.nih.gov). Furthermore, no biallelic inactivating mutations have been found in KCNRG in CLL (pubmed.ncbi.nlm.nih.gov); instead, partial loss and reduced expression appear sufficient to affect cell behavior. This aligns with a model of KCNRG as a haploinsufficient tumor suppressor – even a 50% reduction in its activity might tilt the balance toward unchecked proliferation.

Beyond CLL, the involvement of KCNRG extends to other malignancies:

Mantle Cell Lymphoma (MCL) and Multiple Myeloma (MM) – Similar to CLL, these B-cell tumors often harbor deletions in 13q14.3. Notably, 13q14 deletions are found in about 38% of MCL cases and ~54% of MM cases (pmc.ncbi.nlm.nih.gov). In non-CLL contexts, losing this region (and thus KCNRG and neighboring genes) has been associated with poor prognosis (pmc.ncbi.nlm.nih.gov). This suggests KCNRG loss may contribute to more aggressive disease in lymphoid cancers. The functional importance is supported by in vitro data: KCNRG overexpression can suppress growth of MM cells (e.g., RPMI-8226) and promote cell death (pubmed.ncbi.nlm.nih.gov). In at least one myeloma cell line, a frameshift mutation in KCNRG (a T deletion) was detected, likely disabling its function (pubmed.ncbi.nlm.nih.gov). These data implicate KCNRG as a relevant tumor suppressor across multiple B-cell neoplasms.
Prostate Cancer – Deletions of 13q14 occur in a subset of prostate carcinomas as well (pmc.ncbi.nlm.nih.gov). The discovery paper specifically suggested KCNRG as a candidate prostate tumor suppressor because prostate cancer cell proliferation was sensitive to K⁺ channel blockade (www.sciencedirect.com), and introducing KCNRG mimicked that effect (www.sciencedirect.com). While 13q14 loss is not the predominant alteration in prostate cancer, its occurrence underscores that KCNRG inactivation may contribute to tumor development in the prostate in some cases (pmc.ncbi.nlm.nih.gov). Further research is needed to clarify its role in this context (e.g. whether KCNRG expression correlates with tumor grade or outcomes in prostate cancer).
Hepatocellular Carcinoma (HCC) – A 2006 study systematically examined KCNRG in HCC tumors. Although 13q14 deletions are less common in carcinomas, loss of the KCNRG allele was detected in ~26.5% of HCC cases (17 of 64 informative cases) (www.nature.com). This loss of heterozygosity was significantly associated with more advanced disease: it correlated with presence of intrahepatic metastases, higher tumor grade, and later clinical stage (p<0.03 – 0.008 range) (www.nature.com). Additionally, KCNRG expression was absent in 22 out of 77 HCC tumor samples analyzed, indicating frequent transcriptional silencing (www.nature.com). Importantly, one missense mutation was identified in HCC: an Arg92→His substitution in the BTB domain (www.nature.com). This single-residue change impaired KCNRG’s function – when the mutant form was expressed in liver cells, it had significantly weaker growth-suppressive effect compared to wild-type KCNRG (www.nature.com). The Arg92 residue lies within the conserved BTB/T1 domain, so its alteration likely disrupts KCNRG’s ability to oligomerize or bind K⁺ channel partners. The HCC findings reinforce that genetic or epigenetic inactivation of KCNRG can contribute to tumorigenesis. The consistent pattern across cancers is that loss of KCNRG gives cells a proliferative and survival advantage (conversely, restoring KCNRG restrains growth).
Other Cancers – There are indications that 13q14.3 loss (and by extension KCNRG loss) may occur in other malignancies as well. For instance, deletions in this region have been noted in subsets of gastrointestinal stromal tumors (GIST) (pmc.ncbi.nlm.nih.gov). Large-scale sequencing efforts (TCGA/COSMIC databases) have occasionally found KCNRG mutations in cancers, but these are relatively rare. Aside from the HCC mutation mentioned, KCNRG is not a hotspot for recurrent point mutations in common cancers, supporting the idea that deletion or downregulation is the main mechanism of disruption. A 2021 review on KCTD proteins in cancer highlighted KCNRG as unique among largely uncharacterized KCTDs because its role in cancer is already documented (pmc.ncbi.nlm.nih.gov). The authors noted KCNRG as a negative cell-growth regulator whose loss (via 13q14 deletion) likely contributes to the pathogenesis of CLL and MM (pmc.ncbi.nlm.nih.gov). They also speculated that KCNRG might have broader tumor-suppressive roles yet to be fully explored in other cancers (pmc.ncbi.nlm.nih.gov). Given the evidence, KCNRG is increasingly regarded as part of a multigenic tumor suppressor unit at 13q14, working in concert with other genes (like DLEU2 and miR-15a/16-1) to keep cell proliferation in check (pubmed.ncbi.nlm.nih.gov). The loss of this unit is a driver of malignancy in CLL and possibly other tumors.

Clinical and Diagnostic Implications

The link between KCNRG and disease yields several real-world applications:

Biomarker for Cancer: Detection of 13q14 deletions is routine in CLL diagnostics; FISH cytogenetics or SNP arrays frequently test for this deletion as it has prognostic implications. While the prognostic impact in CLL is partly due to the miR-15a/16-1 loss, KCNRG’s absence may also be contributory. Some studies have suggested that CLL cases with 13q14 deletion (hence KCNRG haploinsufficiency) have distinct gene expression profiles and better outcomes than other cytogenetic subgroups, although they still constitute the majority of cases (pubmed.ncbi.nlm.nih.gov). In multiple myeloma, 13q deletions (including KCNRG) portend a poorer prognosis (pmc.ncbi.nlm.nih.gov), so identifying KCNRG loss could help stratify patients. Moreover, the 2006 HCC study implies KCNRG could be a prognostic marker in liver cancer: loss of the gene was associated with more aggressive tumor behavior (metastasis and high grade) (www.nature.com). If further validated, KCNRG expression status might be useful to gauge tumor aggressiveness in HCC or other solid tumors.
Therapeutic angle: Understanding KCNRG’s function opens up possible therapeutic considerations. One idea is that augmenting KCNRG activity (or mimicking it) might suppress tumor cell growth, similar to using pharmacologic K⁺ channel blockers. For example, Kv1.3 channel blockers are being explored as immune modulators in autoimmune disease and as anti-cancer agents for certain leukemias. KCNRG, as an endogenous inhibitor of Kv channels, could be seen as a natural analog. While delivering a protein is not straightforward, gene therapy or small molecules that enhance KCNRG expression in tumor cells could, in theory, reduce proliferative capacity. Conversely, in conditions where KCNRG might be overactive or detrimental (none are well characterized yet), one might consider inhibiting it. Right now, such therapeutic applications remain speculative since no drugs specifically target KCNRG and its regulatory network.
Autoantibody marker: In APS-1 (autoimmune polyendocrine syndrome type 1), testing for anti-KCNRG antibodies has become a way to identify patients at risk for autoimmune lung disease (pmc.ncbi.nlm.nih.gov). Approximately 7 out of 8 APS-1 patients with unexplained respiratory symptoms had anti-KCNRG autoantibodies, whereas such antibodies were virtually absent in APS-1 patients without lung involvement (pmc.ncbi.nlm.nih.gov). This strong association means that an autoantibody test for KCNRG can serve as a diagnostic clue for APS-1 related pneumonitis. Similarly, in critical care settings, the presence of anti-KCNRG antibodies in ARDS or sepsis could be an interesting indicator of the extent of lung injury or a patient’s immune status (pmc.ncbi.nlm.nih.gov). Burbelo et al. (2010) found that 57% of ARDS patients and 46% of severe sepsis patients developed new autoantibodies during their illness, with KCNRG being the most frequently targeted autoantigen in their panel (pmc.ncbi.nlm.nih.gov). This suggests that KCNRG is highly immunogenic when lung tissues are inflamed or damaged. While these autoantibodies are likely a consequence of tissue damage rather than a cause, they highlight KCNRG’s prominence in lung tissue. Clinically, monitoring such autoantibodies might one day help in understanding or even predicting acute lung injury trajectories, though more research is needed.
Research tool: KCNRG itself can be used as a tool to study K⁺ channel biology. Its specific interaction with Kv channel subunits provides a means to probe channel assembly. Researchers have used KCNRG overexpression or knockdown in cell models to see how it alters the trafficking of Kv1 channels (www.genecards.org). It could be used experimentally to dissect which Kv subtypes are sensitive to its regulation. Furthermore, the distinct difference between KCNRG and most KCTD proteins (in terms of CUL3 binding) makes it an interesting model for studying BTB domain protein interactions – essentially, KCNRG is a BTB-domain protein that chose a channel-regulatory route instead of ubiquitin-ligase route. This could guide structure-function analyses; for instance, swapping domains between KCNRG and a Cullin-binding KCTD might elucidate the structural requirements for each function.

Expert Perspectives and Future Directions

Experts in the field view KCNRG as a partially characterized but significant regulator at the crossroads of ion channel physiology and cancer biology. In a 2021 review of KCTD family proteins, Angrisani et al. highlighted KCNRG as an outlier KCTD with a known role in cancer suppression (pmc.ncbi.nlm.nih.gov). They noted that while many KCTDs are still mysterious, KCNRG stands out because of substantial evidence linking it to tumor suppression in CLL and MM (pmc.ncbi.nlm.nih.gov). The authors point out that enforced KCNRG expression curtails proliferation and survival of leukemia cells, supporting its function as a growth brake (pmc.ncbi.nlm.nih.gov). They also emphasize the correlation of 13q14 deletions with these cancers, underscoring the clinical relevance of losing KCNRG (pmc.ncbi.nlm.nih.gov). In the broader context, there is a growing appreciation that ion channels and their regulators are important in oncology. KCNRG exemplifies this by showing how a modulator of ion flux can influence cell fate. Some oncology researchers propose that targeting ion channels (the so-called “ion channelopathies of cancer”) could open new therapeutic avenues. In that light, KCNRG could be both a biomarker of channel activity in tumors and a model for developing molecules that disrupt channel assembly in cancer cells.

From the immunology perspective, experts were intrigued by the discovery of KCNRG as a dominant autoantigen in APS-1 lung disease (pmc.ncbi.nlm.nih.gov). This revealed an unexpected tissue-restricted expression pattern (bronchial epithelium) and suggested that tolerance to this protein is particularly dependent on the AIRE gene (since APS-1 patients have AIRE mutations). It raises the question of what role KCNRG plays in the lung. Pulmonologists and immunologists might speculate that if KCNRG regulates potassium channels in bronchiolar cells, it could affect processes like electrolyte transport in airway secretions or the proliferation of airway epithelium. There is also an interest in whether KCNRG or anti-KCNRG immune responses contribute to pulmonary conditions outside of APS-1 (for example, could they occur in idiopathic pulmonary fibrosis or other autoimmune lung diseases?). So far, such antibodies have mainly been described in APS-1 and in the context of acute lung injury (ARDS) (pmc.ncbi.nlm.nih.gov), but this remains an area for future investigation.

Moving forward, research in 2023-2024 and beyond is focusing on a few key areas regarding KCNRG:

Structural Biology: With advances like AlphaFold, predictions of KCNRG’s 3D structure (especially its BTB domain) have become available (pmc.ncbi.nlm.nih.gov). Validating these models experimentally (e.g. by crystallography or cryo-EM) could confirm how KCNRG interacts with Kv channel peptides. The 2024 Int. J. Mol. Sci. analysis provided structural models for all KCTD–CUL3 interfaces and found KCNRG to lack a stable interface (pmc.ncbi.nlm.nih.gov), reinforcing the notion that KCNRG’s BTB surface is oriented for channel subunits rather than Cullin. Understanding the precise interaction surfaces on KCNRG that bind channel subunits could facilitate the design of peptides or small molecules that mimic KCNRG’s effect by disrupting channel assembly.
In vivo studies: To date, much of what we know comes from cell-based assays and tumor correlations. A logical next step is to study Kcnrg in animal models. A mouse ortholog of KCNRG exists (sometimes referenced by partial clone names like Dltet or Gm745) (geneglobe.qiagen.com). Generating Kcnrg knockout mice could reveal any phenotype in normal physiology – for instance, do such mice have lymphocyte hyperproliferation, or subtle immunological abnormalities? Conversely, a transgenic mouse overexpressing KCNRG in B-cells might show an immunosuppressed phenotype (e.g. smaller germinal centers, impaired antibody responses). Such models would cement KCNRG’s role in vivo. Similarly, crossing a Kcnrg knockout with a cancer-prone model could test if tumors form more readily. Considering the multi-gene nature of the 13q14 region, one challenge is that deleting only Kcnrg may not recapitulate the full CLL-like phenotype (in CLL, often miR-15/16 are co-deleted). Still, it would clarify KCNRG’s individual contribution.
Cancer genomics and therapy: Ongoing cancer sequencing projects might shed more light on incidence of KCNRG alterations. If, for example, certain lymphoma subtypes without 13q deletion still silence KCNRG (via methylation), it could indicate a broader relevance. Epigenetic drugs or gene reactivation strategies could then be tested to restore KCNRG in tumors. Meanwhile, pharmacologists might explore whether ion channel inhibitors could substitute for KCNRG function in KCNRG-deficient cancers. Since KCNRG specifically downregulates Kv channels, drugs targeting those same channels (like Kv1.3 blockers) might preferentially harm KCNRG-null cancer cells. This approach is speculative but aligns with personalized medicine: patients whose tumors lack KCNRG (and thus have heightened K⁺ channel activity) might respond to K⁺ channel-blocking compounds.

In summary, KCNRG is a distinctive protein that links ion channel regulation to cell proliferation control. Our current understanding is that KCNRG serves as a potassium channel “brake”, keeping cellular K⁺ currents – and thus proliferative signaling – in check. It is predominantly a cytosolic protein with a conserved oligomerization domain that hijacks K⁺ channel assembly processes. Loss of KCNRG unleashes K⁺ channel activity, contributing to uncontrolled cell growth as seen in leukemia, lymphoma, and other cancers. Conversely, high KCNRG activity can dampen cell growth and even trigger cell death, which is why cells normally keep a balance in its expression. Recent research (up to 2024) has reinforced its tumor suppressor credentials and clarified that, unlike many cousins in the KCTD family, KCNRG operates independently of ubiquitin ligases, focusing on channel modulation. As an antigen, it has provided a window into autoimmune lung pathology, stressing its tissue-specific expression. Going forward, KCNRG stands as both a subject of fundamental interest – illuminating how channel regulators impact disease – and a potential target for clinical intervention, whether by measuring its loss as a cancer biomarker or by emulating its function to achieve therapeutic K⁺ channel inhibition.

References: The information above is drawn from current scientific literature and databases, including gene/protein databases (NCBI Gene, UniProt) and a number of key studies. Original discovery and characterization of KCNRG were reported in 2003 (www.sciencedirect.com) (www.sciencedirect.com), with functional tumor suppressor evidence expanded in 2010 (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). The gene’s involvement in HCC was detailed in 2006 (www.nature.com) (www.nature.com). Reviews by expert researchers (e.g., Angrisani et al., 2021 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov)) and recent analyses (Balasco et al., 2024 (pmc.ncbi.nlm.nih.gov)) have been cited to provide up-to-date context. Publication dates and sources have been included with each citation for verification.

Citations

AnnotationURLCitation(end_index=362, start_index=272, title='KCNRG Gene - GeneCards | KCNRG Protein | KCNRG Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNRG#:~:text=,4')
AnnotationURLCitation(end_index=507, start_index=363, title='KCNRG potassium channel regulator [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/283518#:~:text=Summary%20This%20gene%20encodes%20a,24%20other%20tissues%20See%20more')
AnnotationURLCitation(end_index=776, start_index=632, title='KCNRG potassium channel regulator [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/283518#:~:text=Summary%20This%20gene%20encodes%20a,24%20other%20tissues%20See%20more')
AnnotationURLCitation(end_index=1057, start_index=907, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=encoded%20by%20mRNAs%20AY129654%20and,gated%20K')
AnnotationURLCitation(end_index=1297, start_index=1147, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=encoded%20by%20mRNAs%20AY129654%20and,gated%20K')
AnnotationURLCitation(end_index=1640, start_index=1496, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=As%20the%20newly%20found%20gene,gated%20K')
AnnotationURLCitation(end_index=1950, start_index=1806, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=As%20the%20newly%20found%20gene,gated%20K')
AnnotationURLCitation(end_index=2236, start_index=2055, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=match%20at%20L214%20channels%20%28Fig,structure%20in%20the%20KCNRG%20suggested')
AnnotationURLCitation(end_index=2364, start_index=2237, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=voltage,cell%20potassium')
AnnotationURLCitation(end_index=2617, start_index=2467, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=encoded%20by%20mRNAs%20AY129654%20and,gated%20K')
AnnotationURLCitation(end_index=3234, start_index=3144, title='KCNRG Gene - GeneCards | KCNRG Protein | KCNRG Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNRG#:~:text=,4')
AnnotationURLCitation(end_index=3463, start_index=3319, title='KCNRG potassium channel regulator [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/283518#:~:text=Summary%20This%20gene%20encodes%20a,24%20other%20tissues%20See%20more')
AnnotationURLCitation(end_index=3795, start_index=3651, title='KCNRG potassium channel regulator [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/283518#:~:text=This%20gene%20encodes%20a%20protein,24%20other%20tissues%20See%20more')
AnnotationURLCitation(end_index=4092, start_index=3912, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=In%20this%20report%2C%20we%20describe,and%20some%20tumor%20tissues%20analyzed')
AnnotationURLCitation(end_index=4210, start_index=4093, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=As%20voltage,3')
AnnotationURLCitation(end_index=4559, start_index=4368, title='Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2648890/#:~:text=putative%20potassium%20channel%20regulator%20,diagnosis%2C%20characterization%2C%20and%20understanding%20of')
AnnotationURLCitation(end_index=4962, start_index=4771, title='Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2648890/#:~:text=putative%20potassium%20channel%20regulator%20,diagnosis%2C%20characterization%2C%20and%20understanding%20of')
AnnotationURLCitation(end_index=5434, start_index=5267, title='Rapid induction of autoantibodies during ARDS and septic shock - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2970592/#:~:text=From%20screening%20patient%20plasma%2C%2057,the%20last%20serum%20sample%20collected')
AnnotationURLCitation(end_index=5773, start_index=5582, title='Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2648890/#:~:text=putative%20potassium%20channel%20regulator%20,diagnosis%2C%20characterization%2C%20and%20understanding%20of')
AnnotationURLCitation(end_index=6238, start_index=6081, title='KCNRG Gene - GeneCards | KCNRG Protein | KCNRG Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNRG#:~:text=Inhibits%20potassium%20fluxes%20in%20cells,%28%20KCNRG_HUMAN%2CQ8N5I3')
AnnotationURLCitation(end_index=6659, start_index=6519, title='KCNRG Gene - GeneCards | KCNRG Protein | KCNRG Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNRG#:~:text=Signaling%20pathcards,of%20this%20gene%20is%20KCTD12')
AnnotationURLCitation(end_index=7131, start_index=6975, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=isoforms%20that%20are%20expressed%20in,cell%20chronic')
AnnotationURLCitation(end_index=7469, start_index=7313, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=isoforms%20that%20are%20expressed%20in,cell%20chronic')
AnnotationURLCitation(end_index=8026, start_index=7899, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=voltage,cell%20potassium')
AnnotationURLCitation(end_index=8208, start_index=8027, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=match%20at%20L214%20channels%20%28Fig,structure%20in%20the%20KCNRG%20suggested')
AnnotationURLCitation(end_index=8518, start_index=8374, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=As%20the%20newly%20found%20gene,gated%20K')
AnnotationURLCitation(end_index=8919, start_index=8792, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=voltage,cell%20potassium')
AnnotationURLCitation(end_index=9358, start_index=9208, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=encoded%20by%20mRNAs%20AY129654%20and,gated%20K')
AnnotationURLCitation(end_index=9691, start_index=9534, title='KCNRG Gene - GeneCards | KCNRG Protein | KCNRG Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNRG#:~:text=Inhibits%20potassium%20fluxes%20in%20cells,%28%20KCNRG_HUMAN%2CQ8N5I3')
AnnotationURLCitation(end_index=10030, start_index=9873, title='KCNRG Gene - GeneCards | KCNRG Protein | KCNRG Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNRG#:~:text=Inhibits%20potassium%20fluxes%20in%20cells,%28%20KCNRG_HUMAN%2CQ8N5I3')
AnnotationURLCitation(end_index=10507, start_index=10323, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=In%20several%20cell%20types%2C%20enhanced,high%20expression%20of%20EAG%20channels')
AnnotationURLCitation(end_index=10888, start_index=10704, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=In%20several%20cell%20types%2C%20enhanced,high%20expression%20of%20EAG%20channels')
AnnotationURLCitation(end_index=11074, start_index=10889, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=cancer%2C%20LNCaP%20cells%2C%20the%20K,cell%20proliferation%20by%20suppressing%20K')
AnnotationURLCitation(end_index=11343, start_index=11158, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=cancer%2C%20LNCaP%20cells%2C%20the%20K,cell%20proliferation%20by%20suppressing%20K')
AnnotationURLCitation(end_index=11677, start_index=11492, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=cancer%2C%20LNCaP%20cells%2C%20the%20K,cell%20proliferation%20by%20suppressing%20K')
AnnotationURLCitation(end_index=11945, start_index=11784, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=KCNRG%20overexpression%20in%20leukemia%20cell,play%20a%20relevant%20role%20in')
AnnotationURLCitation(end_index=12485, start_index=12316, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=The%20human%20family%20of%20Potassium,between%20family%20members%2C%20capability%20to')
AnnotationURLCitation(end_index=12821, start_index=12665, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10856315/#:~:text=the%20BTB%20domains%20of%20the,unable%20to%20bind%20Cul3%2C%20establish')
AnnotationURLCitation(end_index=13189, start_index=13055, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10856315/#:~:text=KCTD15%5E%7BBTB%28A56,Stable%20complex%20detected')
AnnotationURLCitation(end_index=13460, start_index=13326, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10856315/#:~:text=KCTD15%5E%7BBTB%28A56,Stable%20complex%20detected')
AnnotationURLCitation(end_index=13928, start_index=13794, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10856315/#:~:text=KCTD15%5E%7BBTB%28A56,Stable%20complex%20detected')
AnnotationURLCitation(end_index=14046, start_index=13929, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3', type='url_citation', url='https://www.mdpi.com/1422-0067/25/3/1881#:~:text=,exhibit%20different%20Cul3%20binding%20properties')
AnnotationURLCitation(end_index=14371, start_index=14212, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=The%20KCTD%20proteins%20that%20are,are%20in%20general%20not%20characterized')
AnnotationURLCitation(end_index=15196, start_index=15052, title='KCNRG potassium channel regulator [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/283518#:~:text=This%20gene%20encodes%20a%20protein,24%20other%20tissues%20See%20more')
AnnotationURLCitation(end_index=15922, start_index=15805, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=As%20voltage,3')
AnnotationURLCitation(end_index=17209, start_index=17048, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=KCNRG%20overexpression%20in%20leukemia%20cell,play%20a%20relevant%20role%20in')
AnnotationURLCitation(end_index=17636, start_index=17511, title='Chronic lymphocytic leukemia and 13q14: miRs and more - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/19347735/#:~:text=Loss%20of%20a%20critical%20region,3%20in%20non')
AnnotationURLCitation(end_index=17937, start_index=17812, title='Chronic lymphocytic leukemia and 13q14: miRs and more - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/19347735/#:~:text=Loss%20of%20a%20critical%20region,3%20in%20non')
AnnotationURLCitation(end_index=18237, start_index=18063, title='Chronic lymphocytic leukemia and 13q14: miRs and more - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/19347735/#:~:text=malignant%20cells%20that%20involves%20asynchronous,the%20underlying%20pathomechanism%20of%20CLL')
AnnotationURLCitation(end_index=18715, start_index=18524, title='Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2648890/#:~:text=putative%20potassium%20channel%20regulator%20,diagnosis%2C%20characterization%2C%20and%20understanding%20of')
AnnotationURLCitation(end_index=18883, start_index=18716, title='Rapid induction of autoantibodies during ARDS and septic shock - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2970592/#:~:text=From%20screening%20patient%20plasma%2C%2057,the%20last%20serum%20sample%20collected')
AnnotationURLCitation(end_index=19785, start_index=19660, title='Chronic lymphocytic leukemia and 13q14: miRs and more - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/19347735/#:~:text=Loss%20of%20a%20critical%20region,3%20in%20non')
AnnotationURLCitation(end_index=20224, start_index=20045, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=Previously%20it%20was%20demonstrated%20that,7%5D.%20Four%20candidate%20genes')
AnnotationURLCitation(end_index=20653, start_index=20536, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=As%20voltage,3')
AnnotationURLCitation(end_index=21020, start_index=20865, title='Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/20237900/#:~:text=stable%20overexpression%20of%20KCNRG%20isoforms,at%20least%20in%20a%20subset')
AnnotationURLCitation(end_index=21182, start_index=21021, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=KCNRG%20overexpression%20in%20leukemia%20cell,play%20a%20relevant%20role%20in')
AnnotationURLCitation(end_index=21450, start_index=21289, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=KCNRG%20overexpression%20in%20leukemia%20cell,play%20a%20relevant%20role%20in')
AnnotationURLCitation(end_index=22112, start_index=21970, title='Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/20237900/#:~:text=Three%20MM%20cell%20lines%20and,in%20a%20subset%20of%20patients')
AnnotationURLCitation(end_index=22404, start_index=22262, title='Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/20237900/#:~:text=Three%20MM%20cell%20lines%20and,in%20a%20subset%20of%20patients')
AnnotationURLCitation(end_index=22696, start_index=22535, title='Chronic lymphocytic leukemia and 13q14: miRs and more - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/19347735/#:~:text=Engl%20J%20Med%202000%3B343%3A1910%20,where%20several%20tumor%20suppressor%20genes')
AnnotationURLCitation(end_index=22908, start_index=22783, title='Chronic lymphocytic leukemia and 13q14: miRs and more - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/19347735/#:~:text=Loss%20of%20a%20critical%20region,3%20in%20non')
AnnotationURLCitation(end_index=23599, start_index=23463, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=migration%20capacity%20,of%20CLL%20and%20MM%20tumors')
AnnotationURLCitation(end_index=23860, start_index=23724, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=migration%20capacity%20,of%20CLL%20and%20MM%20tumors')
AnnotationURLCitation(end_index=24258, start_index=24103, title='Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/20237900/#:~:text=stable%20overexpression%20of%20KCNRG%20isoforms,at%20least%20in%20a%20subset')
AnnotationURLCitation(end_index=24527, start_index=24385, title='Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/20237900/#:~:text=Three%20MM%20cell%20lines%20and,in%20a%20subset%20of%20patients')
AnnotationURLCitation(end_index=24807, start_index=24714, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=13q14,128')
AnnotationURLCitation(end_index=25164, start_index=24979, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=cancer%2C%20LNCaP%20cells%2C%20the%20K,cell%20proliferation%20by%20suppressing%20K')
AnnotationURLCitation(end_index=25326, start_index=25209, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=As%20voltage,3')
AnnotationURLCitation(end_index=25609, start_index=25516, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=13q14,128')
AnnotationURLCitation(end_index=26170, start_index=26014, title='Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas | Experimental & Molecular Medicine', type='url_citation', url='https://www.nature.com/articles/emm200630#:~:text=KCNRG%20missense%20mutation%2C%20CGT%E2%86%92CAT%20,of%20expression%20of%20the%20KCNRG')
AnnotationURLCitation(end_index=26537, start_index=26381, title='Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas | Experimental & Molecular Medicine', type='url_citation', url='https://www.nature.com/articles/emm200630#:~:text=KCNRG%20missense%20mutation%2C%20CGT%E2%86%92CAT%20,of%20expression%20of%20the%20KCNRG')
AnnotationURLCitation(end_index=26831, start_index=26675, title='Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas | Experimental & Molecular Medicine', type='url_citation', url='https://www.nature.com/articles/emm200630#:~:text=Moreover%2C%20the%20allelic%20loss%20was,development%20and%2For%20progression%20of%20a')
AnnotationURLCitation(end_index=27091, start_index=26939, title='Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas | Experimental & Molecular Medicine', type='url_citation', url='https://www.nature.com/articles/emm200630#:~:text=The%20potassium%20channels%20are%20ubiquitous,Interestingly%2C%20the%20suppressive')
AnnotationURLCitation(end_index=27404, start_index=27281, title='Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas | Experimental & Molecular Medicine', type='url_citation', url='https://www.nature.com/articles/emm200630#:~:text=allelic%20loss%20and%20expression%20patterns,positive')
AnnotationURLCitation(end_index=28170, start_index=28077, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=13q14,128')
AnnotationURLCitation(end_index=28834, start_index=28672, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=Among%20them%2C%20KCNRG%20is%20the,cancer%20is%20known%2C%20albeit%20partially')
AnnotationURLCitation(end_index=29142, start_index=28981, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=KCNRG%20overexpression%20in%20leukemia%20cell,play%20a%20relevant%20role%20in')
AnnotationURLCitation(end_index=29397, start_index=29261, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=migration%20capacity%20,of%20CLL%20and%20MM%20tumors')
AnnotationURLCitation(end_index=29777, start_index=29612, title='Chronic lymphocytic leukemia and 13q14: miRs and more - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/19347735/#:~:text=malignant%20cells%20that%20involves%20asynchronous,3%20candidate%20genes%20will%20shed')
AnnotationURLCitation(end_index=30654, start_index=30529, title='Chronic lymphocytic leukemia and 13q14: miRs and more - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/19347735/#:~:text=Loss%20of%20a%20critical%20region,3%20in%20non')
AnnotationURLCitation(end_index=30872, start_index=30736, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=migration%20capacity%20,of%20CLL%20and%20MM%20tumors')
AnnotationURLCitation(end_index=31275, start_index=31119, title='Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas | Experimental & Molecular Medicine', type='url_citation', url='https://www.nature.com/articles/emm200630#:~:text=KCNRG%20missense%20mutation%2C%20CGT%E2%86%92CAT%20,of%20expression%20of%20the%20KCNRG')
AnnotationURLCitation(end_index=32714, start_index=32523, title='Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2648890/#:~:text=putative%20potassium%20channel%20regulator%20,diagnosis%2C%20characterization%2C%20and%20understanding%20of')
AnnotationURLCitation(end_index=33105, start_index=32914, title='Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2648890/#:~:text=putative%20potassium%20channel%20regulator%20,diagnosis%2C%20characterization%2C%20and%20understanding%20of')
AnnotationURLCitation(end_index=33592, start_index=33425, title='Rapid induction of autoantibodies during ARDS and septic shock - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2970592/#:~:text=From%20screening%20patient%20plasma%2C%2057,the%20last%20serum%20sample%20collected')
AnnotationURLCitation(end_index=33977, start_index=33810, title='Rapid induction of autoantibodies during ARDS and septic shock - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2970592/#:~:text=From%20screening%20patient%20plasma%2C%2057,the%20last%20serum%20sample%20collected')
AnnotationURLCitation(end_index=34832, start_index=34675, title='KCNRG Gene - GeneCards | KCNRG Protein | KCNRG Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNRG#:~:text=Inhibits%20potassium%20fluxes%20in%20cells,%28%20KCNRG_HUMAN%2CQ8N5I3')
AnnotationURLCitation(end_index=35913, start_index=35751, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=Among%20them%2C%20KCNRG%20is%20the,cancer%20is%20known%2C%20albeit%20partially')
AnnotationURLCitation(end_index=36226, start_index=36065, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=KCNRG%20overexpression%20in%20leukemia%20cell,play%20a%20relevant%20role%20in')
AnnotationURLCitation(end_index=36543, start_index=36382, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=KCNRG%20overexpression%20in%20leukemia%20cell,play%20a%20relevant%20role%20in')
AnnotationURLCitation(end_index=36808, start_index=36672, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=migration%20capacity%20,of%20CLL%20and%20MM%20tumors')
AnnotationURLCitation(end_index=37660, start_index=37469, title='Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2648890/#:~:text=putative%20potassium%20channel%20regulator%20,diagnosis%2C%20characterization%2C%20and%20understanding%20of')
AnnotationURLCitation(end_index=38675, start_index=38508, title='Rapid induction of autoantibodies during ARDS and septic shock - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2970592/#:~:text=From%20screening%20patient%20plasma%2C%2057,the%20last%20serum%20sample%20collected')
AnnotationURLCitation(end_index=39167, start_index=38973, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10856315/#:~:text=KCTD%20%28%28K%29potassium%20Channel%20Tetramerization%20Domain,demonstrate%20the%20impressive%20ability%20of')
AnnotationURLCitation(end_index=39576, start_index=39442, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10856315/#:~:text=KCTD15%5E%7BBTB%28A56,Stable%20complex%20detected')
AnnotationURLCitation(end_index=40285, start_index=40149, title='KCNRG [Human] | GeneGlobe', type='url_citation', url='https://geneglobe.qiagen.com/us/knowledge/gene/ENSG00000198553#:~:text=Aliases%20%20,Human%2C%20Homo%20sapiens')
AnnotationURLCitation(end_index=43656, start_index=43476, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=In%20this%20report%2C%20we%20describe,and%20some%20tumor%20tissues%20analyzed')
AnnotationURLCitation(end_index=43774, start_index=43657, title='A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3 - ScienceDirect', type='url_citation', url='https://www.sciencedirect.com/science/article/pii/S0014579303002114#:~:text=As%20voltage,3')
AnnotationURLCitation(end_index=43990, start_index=43835, title='Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/20237900/#:~:text=stable%20overexpression%20of%20KCNRG%20isoforms,at%20least%20in%20a%20subset')
AnnotationURLCitation(end_index=44133, start_index=43991, title='Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/20237900/#:~:text=Three%20MM%20cell%20lines%20and,in%20a%20subset%20of%20patients')
AnnotationURLCitation(end_index=44309, start_index=44186, title='Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas | Experimental & Molecular Medicine', type='url_citation', url='https://www.nature.com/articles/emm200630#:~:text=allelic%20loss%20and%20expression%20patterns,positive')
AnnotationURLCitation(end_index=44466, start_index=44310, title='Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas | Experimental & Molecular Medicine', type='url_citation', url='https://www.nature.com/articles/emm200630#:~:text=Moreover%2C%20the%20allelic%20loss%20was,development%20and%2For%20progression%20of%20a')
AnnotationURLCitation(end_index=44692, start_index=44530, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=Among%20them%2C%20KCNRG%20is%20the,cancer%20is%20known%2C%20albeit%20partially')
AnnotationURLCitation(end_index=44854, start_index=44693, title='The emerging role of the KCTD proteins in cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC8127222/#:~:text=KCNRG%20overexpression%20in%20leukemia%20cell,play%20a%20relevant%20role%20in')
AnnotationURLCitation(end_index=45034, start_index=44900, title='A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3 - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10856315/#:~:text=KCTD15%5E%7BBTB%28A56,Stable%20complex%20detected')