id: Q5HYA8
gene_symbol: TMEM67
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TMEM67 (meckelin/MKS3) is a single-pass transmembrane protein that localizes to
  the ciliary transition zone and is a core component of the MKS complex (Meckel
  syndrome complex). Its domain architecture comprises an N-terminal extracellular
  region containing a cysteine-rich domain (CRD) homologous to Frizzled/ROR
  receptors (a Wnt-binding module), a beta-sheet-rich domain, an extracellular
  linker region containing ADAMTS9 cleavage sites, a transmembrane domain, and a
  cytoplasmic tail with coiled-coil features mediating protein-protein interactions
  (DOI:10.1101/2024.09.04.611229). A major mechanistic advance identifies TMEM67
  as a proteolytic substrate of the metalloproteinase ADAMTS9, generating two
  functional forms: a released N-terminal ectodomain fragment proposed to modulate
  Wnt signaling, and a C-terminal fragment (Delta342) that localizes to the TZ and
  supports ciliogenesis/TZ assembly (DOI:10.1101/2024.09.04.611229). This
  cleavage-based functional partitioning explains how different alleles may
  differentially affect ciliary gating versus signaling outputs. TMEM67 is essential
  for primary cilium formation and structure, acting in centrosome migration to the
  apical cell surface during early ciliogenesis. Loss of TMEM67 or ADAMTS9 reduces
  recruitment of multiple MKS/B9 module proteins (TCTN1/2/3, TMEM237, CC2D2A, B9D2)
  to mature basal bodies/TZ, positioning TMEM67 as a central organizer within
  MKS-related TZ assemblies. TMEM67 functions as a receptor or co-receptor in
  non-canonical Wnt signaling (interacting with WNT5A and ROR2), and plays a role
  in epithelial branching morphogenesis. It also participates in endoplasmic
  reticulum-associated degradation (ERAD) of misfolded surfactant protein C
  (SFTPC), where it acts as an adaptor linking the ER lumenal quality control
  machinery with the cytosolic degradation apparatus. TMEM67 is the most commonly
  mutated gene in MKS, accounting for approximately 16-20% of MKS cases
  (DOI:10.1101/2024.09.04.611229). Mutations in TMEM67 cause a spectrum of
  ciliopathies including Meckel-Gruber syndrome (MKS3), Joubert syndrome (JBTS6),
  COACH syndrome, nephronophthisis (NPHP11), Bardet-Biedl syndrome (BBS14), and
  RHYNS syndrome. TMEM67 pathogenic variants contribute to around 80% of JS-related
  disorders featuring liver involvement (DOI:10.54029/2024wir).
existing_annotations:
- term:
    id: GO:0035869
    label: ciliary transition zone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation placing TMEM67 at the ciliary transition zone, inferred by
      phylogenetic analysis (PANTHER). TMEM67 is a well-established component of
      the MKS-JBTS module at the ciliary transition zone. Multiple publications
      confirm this localization. PMID:22121117 states that meckelin "Localizes at
      the transition zone, a region between the basal body and the ciliary axoneme."
      PMID:26595381 directly demonstrated transition zone localization by IDA.
      PMID:34964473 describes TMEM67/MKS3 as "a transmembrane protein that functions
      at the ciliary transition zone." This is a core localization for this protein.
    action: ACCEPT
    reason: >-
      Transition zone localization is the best-established and most central
      subcellular localization for TMEM67. It is supported by extensive experimental
      evidence (IDA in PMID:26595381, NAS from PMID:22179047) and by the IBA
      phylogenetic inference. This is a core annotation.
    supported_by:
      - reference_id: PMID:26595381
        supporting_text: >-
          TMEM107 recruits ciliopathy proteins to subdomains of the ciliary
          transition zone and causes Joubert syndrome.
      - reference_id: PMID:34964473
        supporting_text: >-
          TMEM67/MKS3 is a transmembrane protein that functions at the ciliary
          transition zone (TZ), which corresponds to the proximal-most
          0.2–1.0 μm of the ciliary axoneme
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cilium assembly, inferred by phylogenetic analysis
      (PANTHER). TMEM67 is required for ciliogenesis. PMID:17185389 demonstrated
      that "siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated
      epithelial cell-line blocked centriole migration to the apical membrane and
      consequent formation of the primary cilium." PMID:19515853 showed that "MKS1
      and MKS3 functions are required for ciliary structure and function." This is a
      core biological process for TMEM67.
    action: ACCEPT
    reason: >-
      Cilium assembly is a core function of TMEM67. It is supported by extensive
      experimental evidence including IMP from PMID:19515853 and knockdown data
      from PMID:17185389. The IBA annotation is fully consistent with published data.
    supported_by:
      - reference_id: PMID:17185389
        supporting_text: >-
          siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated
          epithelial cell-line blocked centriole migration to the apical membrane
          and consequent formation of the primary cilium.
      - reference_id: PMID:19515853
        supporting_text: >-
          MKS1 and MKS3 functions are required for ciliary structure and function,
          including a role in regulating length and appropriate number through
          modulating centrosome duplication.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation mapping TMEM67 to the ER membrane based on UniProt subcellular
      location vocabulary. PMID:19815549 (Wang et al. 2009) directly demonstrated
      that "MKS3 was identified as a membrane glycoprotein predominantly localized to
      the ER." This IEA is consistent with the IDA annotation from the same paper.
      However, the ER membrane localization represents a secondary localization; the
      primary localization is the ciliary transition zone.
    action: ACCEPT
    reason: >-
      ER membrane localization is supported by direct experimental evidence
      (IDA, PMID:19815549). The IEA correctly captures this localization. While ER
      is not the primary localization of TMEM67 (the ciliary transition zone is),
      TMEM67 does reside at the ER membrane where it functions in ERAD.
    supported_by:
      - reference_id: PMID:19815549
        supporting_text: >-
          MKS3 was identified as a membrane glycoprotein predominantly localized to
          the ER.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation mapping TMEM67 to the plasma membrane based on UniProt
      subcellular location vocabulary. PMID:17185389 showed that "meckelin localized
      both to the primary cilium and to the plasma membrane in ciliated cell-lines
      and primary cells." The UniProt record states "Cell membrane" as a subcellular
      location. This is a valid but secondary localization relative to the ciliary
      transition zone.
    action: ACCEPT
    reason: >-
      Plasma membrane localization is experimentally supported by PMID:17185389,
      which showed meckelin at both the primary cilium and the plasma membrane.
      This IEA is correct, though the ciliary transition zone is the more specific
      and informative localization.
    supported_by:
      - reference_id: PMID:17185389
        supporting_text: >-
          meckelin localized both to the primary cilium and to the plasma membrane
          in ciliated cell-lines and primary cells.
- term:
    id: GO:0005929
    label: cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation mapping TMEM67 to the cilium based on UniProt subcellular
      location vocabulary. PMID:17185389 confirmed that meckelin localizes to the
      primary cilium. The UniProt record lists "Cell projection, cilium" as a
      subcellular location. This is correct but less specific than the ciliary
      transition zone (GO:0035869), which is the more precise localization supported
      by IDA evidence in PMID:26595381.
    action: ACCEPT
    reason: >-
      Cilium localization is correct and supported by experimental evidence. While
      the ciliary transition zone is more specific, the broader cilium term from an
      IEA is acceptable as it is not incorrect. It is a parent-like term relative to
      the more specific transition zone annotation.
    supported_by:
      - reference_id: PMID:17185389
        supporting_text: >-
          meckelin localized both to the primary cilium and to the plasma membrane
          in ciliated cell-lines and primary cells.
- term:
    id: GO:0030030
    label: cell projection organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation mapping TMEM67 to cell projection organization based on
      UniProtKB/Swiss-Prot keyword mapping. This is a broad term. TMEM67 is
      indeed involved in organizing the cilium (a cell projection) through its role
      in ciliogenesis. This annotation is not wrong but is very general compared to
      the more specific cilium assembly (GO:0060271) annotation.
    action: ACCEPT
    reason: >-
      While very general, this IEA mapping is not incorrect. TMEM67 is involved in
      cilium organization, which is a form of cell projection organization. The more
      specific cilium assembly annotation exists separately. For an IEA, this level
      of generality is acceptable.
- term:
    id: GO:0036038
    label: MKS complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation placing TMEM67 as part of the MKS complex, based on InterPro
      domain mapping (IPR019170). TMEM67 is a well-established core component of the
      MKS-JBTS module at the ciliary transition zone. PMID:22179047 identified this
      complex and PMID:26035863 describes TMEM67 as "a component of the MKS-JBTS
      module at the transition zone." PMID:34731008 also discusses TMEM67 as part of
      the MKS-JBTS module.
    action: ACCEPT
    reason: >-
      MKS complex membership is a core annotation for TMEM67. It is well supported
      by multiple publications and is also annotated by ISS (GO_REF:0000024). The
      IEA via InterPro is correct.
    supported_by:
      - reference_id: PMID:26035863
        supporting_text: >-
          TMEM67 is a component of the MKS-JBTS module at the transition zone.
      - reference_id: PMID:22179047
        supporting_text: >-
          Using RNAi screening, proteomics, cell biological and mouse genetics
          approaches, we have identified a complex of nine proteins, seven of which
          are disrupted in human ciliopathies.
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for cilium assembly based on InterPro domain mapping
      (IPR019170). This is a duplicate of the IBA annotation for the same GO term.
      The annotation is correct; TMEM67 is required for ciliogenesis as demonstrated
      in PMID:17185389 and PMID:19515853.
    action: ACCEPT
    reason: >-
      This IEA is correct and consistent with the IBA and IMP annotations for the
      same term. Cilium assembly is a core function of TMEM67.
    supported_by:
      - reference_id: PMID:17185389
        supporting_text: >-
          siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated
          epithelial cell-line blocked centriole migration to the apical membrane
          and consequent formation of the primary cilium.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      Protein binding annotation based on a high-throughput yeast two-hybrid (Y2H)
      interactome mapping study (PMID:32814053, Haenig et al. 2020). The WITH/FROM
      field indicates UniProtKB:P05067-2 (APP isoform 2, amyloid precursor protein).
      This study was a large-scale screen focused on neurodegenerative disease
      proteins. The interaction between TMEM67 and APP has no obvious biological
      context and may represent a false positive from the high-throughput screen.
      The IntAct database records 3 experiments for this interaction. The "protein
      binding" term is uninformative.
    action: REMOVE
    reason: >-
      The generic "protein binding" annotation does not convey any useful
      information about TMEM67 function. The interaction with APP from a
      high-throughput Y2H screen lacks biological context for TMEM67 function.
      No more specific replacement term is available. The interaction likely
      reflects overexpression artifacts in the Y2H system rather than a
      biologically meaningful function of TMEM67.
- term:
    id: GO:0035869
    label: ciliary transition zone
  evidence_type: NAS
  original_reference_id: PMID:22179047
  review:
    summary: >-
      NAS annotation for ciliary transition zone localization from the ComplexPortal,
      citing PMID:22179047 (Chih et al. 2011). This paper identified a complex of
      nine proteins at the transition zone, including TMEM231, B9D1, and CC2D2A,
      that forms a diffusion barrier essential for normal cilia function. While the
      paper studied the broader complex (and TMEM67 is part of the MKS module),
      TMEM67 transition zone localization is well established by other evidence
      (IDA in PMID:26595381, IBA from GO_REF:0000033).
    action: ACCEPT
    reason: >-
      The transition zone localization of TMEM67 is a core annotation supported
      by multiple evidence types. This NAS from ComplexPortal is consistent with
      direct evidence from IDA (PMID:26595381) and IBA (GO_REF:0000033).
    supported_by:
      - reference_id: PMID:22179047
        supporting_text: >-
          Disruption of the complex in vitro causes a reduction in cilia formation
          and a loss of signalling receptors from the remaining cilia.
- term:
    id: GO:1904491
    label: protein localization to ciliary transition zone
  evidence_type: NAS
  original_reference_id: PMID:22179047
  review:
    summary: >-
      NAS annotation for protein localization to the ciliary transition zone from
      the ComplexPortal, citing PMID:22179047 (Chih et al. 2011). The paper showed
      that the MKS complex components depend on each other for transition zone
      localization: "The localizations of TMEM231, B9D1 and CC2D2A at the transition
      zone are dependent on one another." TMEM67 as a member of this complex
      participates in the mutual localization and recruitment of transition zone
      proteins. PMID:26595381 further showed that TMEM107 recruits ciliopathy
      proteins including MKS module members to transition zone subdomains.
    action: ACCEPT
    reason: >-
      TMEM67 is a core component of the MKS module that participates in the
      recruitment and localization of proteins to the ciliary transition zone. This
      biological process annotation is well supported by the mutual dependence of
      MKS complex members for their transition zone localization.
    supported_by:
      - reference_id: PMID:22179047
        supporting_text: >-
          The localizations of TMEM231, B9D1 (B9 domain-containing protein 1)
          and CC2D2A (coiled-coil and C2 domain-containing protein 2A) at the
          transition zone are dependent on one another and on Sept2.
      - reference_id: PMID:26595381
        supporting_text: >-
          nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS
          module by organizing recruitment of the ciliopathy proteins MKS-1,
          TMEM-231 (JBTS20) and JBTS-14 (TMEM237).
- term:
    id: GO:0035567
    label: non-canonical Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:34964473
  review:
    summary: >-
      IMP annotation for non-canonical Wnt signaling pathway, based on
      PMID:34964473 (Lange et al. 2022). This paper used C. elegans CRISPR knock-in
      models of TMEM67 patient variants to demonstrate functional effects on
      cilia-dependent phenotypes. The validation was done using a genetic
      complementation assay in human TMEM67 knockout hTERT-RPE1 cells that "tests a
      TMEM67 signalling function." The role of TMEM67 in non-canonical Wnt signaling
      is most extensively characterized in PMID:26035863 (Abdelhamed et al. 2015),
      which showed that "TMEM67 is a receptor that has a main role in non-canonical
      Wnt signalling, mediated by Wnt5a and ROR2."
    action: ACCEPT
    reason: >-
      Non-canonical Wnt signaling is a core function of TMEM67. PMID:26035863
      extensively characterized TMEM67 as a receptor in the Wnt5a-TMEM67-ROR2
      signaling axis. PMID:34964473 provided additional functional validation.
      The structural study PMID:34731008 confirmed Wnt5a binding to the extracellular
      domain of TMEM67.
    supported_by:
      - reference_id: PMID:26035863
        supporting_text: >-
          We propose that TMEM67 is a receptor that has a main role in non-canonical
          Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh
          signalling.
      - reference_id: PMID:26035863
        supporting_text: >-
          TMEM67 (meckelin) is essential for phosphorylation of the non-canonical
          Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2)
          upon stimulation with Wnt5a-conditioned medium.
      - reference_id: PMID:34731008
        supporting_text: >-
          Recently, it has been suggested that Meckelin can function as a receptor
          of β-catenin–independent signaling that binds to Wnt5a and mediates
          downstream signaling through receptor tyrosine kinase-like orphan
          receptor 2 as a coreceptor, thereby controlling basal body positioning
          and epithelial branching morphogenesis (12).
    additional_reference_ids:
      - PMID:26035863
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26035863
  review:
    summary: >-
      Protein binding annotation based on PMID:26035863 (Abdelhamed et al. 2015),
      with WITH/FROM UniProtKB:Q01974 (ROR2). This paper demonstrated that "ROR2
      also colocalises and interacts with TMEM67 at the ciliary transition zone."
      The interaction between TMEM67 and ROR2 is functionally significant: TMEM67
      acts as a co-receptor with ROR2 in non-canonical Wnt signaling. The generic
      "protein binding" term does not capture this specific and important functional
      relationship.
    action: MODIFY
    reason: >-
      The interaction with ROR2 is a functionally significant co-receptor
      interaction in the non-canonical Wnt signaling pathway, not merely generic
      protein binding. A more specific term capturing receptor/co-receptor function
      in Wnt signaling would be more informative than generic protein binding.
    proposed_replacement_terms:
      - id: GO:0005102
        label: signaling receptor binding
    supported_by:
      - reference_id: PMID:26035863
        supporting_text: >-
          ROR2 also colocalises and interacts with TMEM67 at the ciliary transition
          zone.
      - reference_id: PMID:26035863
        supporting_text: >-
          TMEM67 (meckelin) is essential for phosphorylation of the non-canonical
          Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2)
          upon stimulation with Wnt5a-conditioned medium.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34731008
  review:
    summary: >-
      Protein binding annotation based on PMID:34731008 (Liu et al. 2021), with
      WITH/FROM UniProtKB:P41221 (WNT5A). This structural study demonstrated
      the cryo-EM structure of meckelin and confirmed that the extracellular
      CRD domain binds WNT5A. PMID:26035863 had previously shown that "the
      extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a
      in an in vitro binding assay." This is a critical functional interaction.
      The generic "protein binding" term does not capture the Wnt ligand binding
      activity.
    action: MODIFY
    reason: >-
      The interaction with WNT5A represents a specific Wnt ligand binding activity
      central to TMEM67 function as a non-canonical Wnt receptor. A more specific
      molecular function term should be used.
    proposed_replacement_terms:
      - id: GO:0017147
        label: Wnt-protein binding
    supported_by:
      - reference_id: PMID:34731008
        supporting_text: >-
          Recently, it has been suggested that Meckelin can function as a receptor
          of β-catenin–independent signaling that binds to Wnt5a and mediates
          downstream signaling through receptor tyrosine kinase-like orphan
          receptor 2 as a coreceptor, thereby controlling basal body positioning
          and epithelial branching morphogenesis (12).
      - reference_id: PMID:26035863
        supporting_text: >-
          the extracellular N-terminal domain of TMEM67 preferentially binds to
          Wnt5a in an in vitro binding assay.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35137054
  review:
    summary: >-
      Protein binding annotation based on PMID:35137054 (Epting et al. 2022), with
      WITH/FROM UniProtKB:A2RU14 (TMEM218). This paper identified TMEM218 as a
      major component of the ciliary transition zone module and showed that
      "Co-immunoprecipitation assays resulted in the physical interaction of
      TMEM218 with the MKS module member TMEM67/Meckelin." This interaction is
      relevant to transition zone complex formation.
    action: KEEP_AS_NON_CORE
    reason: >-
      The interaction with TMEM218 reflects the assembly of the MKS transition
      zone complex. Generic "protein binding" is uninformative, but no ideal
      replacement MF term exists. The interaction is already captured by the CC
      annotation GO:0036038 (MKS complex). Keeping as non-core since the
      WITH/FROM data documents the specific TMEM218 interaction partner.
    supported_by:
      - reference_id: PMID:35137054
        supporting_text: >-
          Co-immunoprecipitation assays resulted in the physical interaction of
          TMEM218 with the MKS module member TMEM67/Meckelin that was
          significantly reduced by the TMEM218 missense change harboured by
          one of our patients.
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for cilium assembly, transferred from mouse ortholog
      (UniProtKB:Q8BR76). This is consistent with the IBA (GO_REF:0000033) and
      IMP (PMID:19515853) annotations for the same term. Cilium assembly is a
      well-established core function of TMEM67.
    action: ACCEPT
    reason: >-
      The ISS annotation is consistent with experimental evidence from human and
      model organisms. Cilium assembly is a core function of TMEM67 supported by
      multiple evidence types.
- term:
    id: GO:0035869
    label: ciliary transition zone
  evidence_type: IDA
  original_reference_id: PMID:26595381
  review:
    summary: >-
      IDA annotation for ciliary transition zone localization from PMID:26595381
      (Lambacher et al. 2016). This study used super-resolution microscopy in
      C. elegans and mammalian cells to characterize MKS module protein
      localizations within transition zone subdomains. The study showed that
      "MKS module membrane proteins are immobile and super-resolution microscopy
      in worms and mammalian cells reveals periodic localizations within the TZ."
      This provides direct evidence for TMEM67 localization at the transition zone.
    action: ACCEPT
    reason: >-
      Direct experimental evidence (IDA) for the core localization of TMEM67 at
      the ciliary transition zone. This is the strongest evidence type for this
      annotation and confirms the transition zone as the primary subcellular
      localization of TMEM67.
    supported_by:
      - reference_id: PMID:26595381
        supporting_text: >-
          MKS module membrane proteins are immobile and super-resolution microscopy
          in worms and mammalian cells reveals periodic localizations within the TZ.
- term:
    id: GO:0060170
    label: ciliary membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5617816
  review:
    summary: >-
      TAS annotation from Reactome pathway R-HSA-5617816 (RAB3IP stimulates
      nucleotide exchange on RAB8A). TMEM67 is placed at the ciliary membrane in
      the context of cilium assembly pathways. TMEM67 is a transmembrane protein
      that spans the ciliary membrane at the transition zone. This annotation is
      correct but less specific than transition zone.
    action: ACCEPT
    reason: >-
      Ciliary membrane is a valid localization for TMEM67 as a transmembrane protein
      that spans the ciliary membrane at the transition zone. The Reactome pathway
      context is appropriate. While the transition zone is more specific, the ciliary
      membrane annotation is not wrong.
    supported_by:
      - reference_id: PMID:17185389
        supporting_text: >-
          meckelin localized both to the primary cilium and to the plasma membrane
          in ciliated cell-lines and primary cells.
- term:
    id: GO:0060170
    label: ciliary membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5626681
  review:
    summary: >-
      TAS annotation from Reactome pathway R-HSA-5626681 (Recruitment of transition
      zone proteins). TMEM67 placed at the ciliary membrane in the context of
      transition zone protein recruitment. This is a duplicate of the same GO term
      with a different Reactome source.
    action: ACCEPT
    reason: >-
      Same as other ciliary membrane annotations. This Reactome pathway context
      (transition zone protein recruitment) is particularly relevant for TMEM67
      as a core transition zone component.
- term:
    id: GO:0060170
    label: ciliary membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5638009
  review:
    summary: >-
      TAS annotation from Reactome pathway R-HSA-5638009 (CEP164 recruits
      RAB3IP-carrying Golgi-derived vesicles to the basal body). TMEM67 placed at
      the ciliary membrane in the context of vesicle recruitment to the basal body.
      This is a third Reactome pathway source for the same GO term.
    action: ACCEPT
    reason: >-
      Same as other ciliary membrane annotations. The annotation is correct as
      TMEM67 is a transmembrane protein at the ciliary membrane.
- term:
    id: GO:0031005
    label: filamin binding
  evidence_type: IPI
  original_reference_id: PMID:22121117
  review:
    summary: >-
      IPI annotation for filamin binding, based on PMID:22121117 (Adams et al.
      2012) with WITH/FROM UniProtKB:P21333 (FLNA, filamin A). This paper
      demonstrated that "the cytoplasmic domain of meckelin directly interacts
      with the actin-binding protein filamin A" and that this interaction mediates
      ciliogenesis. An in-frame deletion mutation in the meckelin C-terminus
      "abrogate[d] the meckelin-filamin A interaction." The study showed that
      "loss of filamin A by siRNA knockdown, in patient cells, and in tissues from
      Flna null mouse embryos results in cellular phenotypes identical to those
      caused by meckelin loss, namely basal body positioning and ciliogenesis
      defects." This is a specific and well-characterized molecular function.
    action: ACCEPT
    reason: >-
      Filamin binding is a well-characterized molecular function of TMEM67 that is
      directly relevant to its role in ciliogenesis and basal body positioning.
      Unlike generic "protein binding," this term is specific and informative. The
      interaction is direct and functionally significant.
    supported_by:
      - reference_id: PMID:22121117
        supporting_text: >-
          the cytoplasmic domain of meckelin directly interacts with the
          actin-binding protein filamin A, potentially at the apical cell surface
          associated with the basal body.
      - reference_id: PMID:22121117
        supporting_text: >-
          loss of filamin A by siRNA knockdown, in patient cells, and in tissues
          from Flna(Dilp2) null mouse embryos results in cellular phenotypes
          identical to those caused by meckelin loss, namely basal body positioning
          and ciliogenesis defects.
- term:
    id: GO:0036038
    label: MKS complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for MKS complex membership, transferred from mouse ortholog
      (UniProtKB:Q8BR76). TMEM67 is a well-established component of the MKS
      complex (tectonic-like/B9 complex) at the transition zone. This is consistent
      with the IEA annotation from InterPro and supported by multiple publications
      (PMID:22179047, PMID:26035863, PMID:34731008).
    action: ACCEPT
    reason: >-
      MKS complex membership is a core annotation for TMEM67. The ISS transfer
      from mouse is well supported by human experimental data and consistent with
      the IEA from InterPro.
    supported_by:
      - reference_id: PMID:26035863
        supporting_text: >-
          TMEM67 is a component of the MKS-JBTS module at the transition zone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17185389
  review:
    summary: >-
      Protein binding annotation based on PMID:17185389 (Dawe et al. 2007) with
      WITH/FROM UniProtKB:Q9NXB0 (MKS1). The paper demonstrated by
      co-immunoprecipitation that "wild-type meckelin and MKS1 interact." This
      interaction between TMEM67 and MKS1 is relevant to the MKS complex at
      the transition zone. The generic "protein binding" term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      The interaction with MKS1 reflects MKS transition zone complex formation.
      Generic protein binding does not capture this specific relationship. The
      interaction is already represented by the MKS complex annotation
      (GO:0036038). No better MF term is available, so this is kept as non-core
      since the WITH/FROM data documents the specific MKS1 interaction partner.
    supported_by:
      - reference_id: PMID:17185389
        supporting_text: >-
          Co-immunoprecipitation experiments show that wild-type meckelin and MKS1
          interact and, in three-dimensional tissue culture assays, epithelial
          branching morphogenesis was severely impaired.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19815549
  review:
    summary: >-
      Protein binding annotation based on PMID:19815549 (Wang et al. 2009). The GOA
      file shows three separate protein binding entries for this PMID with different
      WITH/FROM fields: UniProtKB:P08582, UniProtKB:Q8IXB1 (DNAJC10/ERdj5), and
      UniProtKB:Q9UBS3 (DNAJB9/ERdj4). This YAML entry represents the interactions
      of TMEM67 with ERAD-associated proteins. The paper showed that "The ER lumenal
      domain of MKS3 interacted with a complex that included mutant SP-C and
      associated chaperones, whereas the region predicted to encode the transmembrane
      domains of MKS3 interacted with cytosolic p97." These interactions reflect
      TMEM67 adaptor function in ERAD rather than a generic protein binding activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      The interactions with ERAD components (DNAJB9, DNAJC10, and related proteins)
      document TMEM67 participation in ERAD as an adaptor. While "protein binding"
      is uninformative, the WITH/FROM data provide useful documentation of the ERAD
      interaction partners. This is a non-core function of TMEM67 (ERAD adaptor)
      compared to its primary role at the ciliary transition zone. The ERAD pathway
      biological process annotation (GO:0036503) better captures this role.
    supported_by:
      - reference_id: PMID:19815549
        supporting_text: >-
          The ER lumenal domain of MKS3 interacted with a complex that included
          mutant SP-C and associated chaperones, whereas the region predicted to
          encode the transmembrane domains of MKS3 interacted with cytosolic p97.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:19815549
  review:
    summary: >-
      IDA annotation for ER membrane localization from PMID:19815549 (Wang et al.
      2009). The paper identified "MKS3 was identified as a membrane glycoprotein
      predominantly localized to the ER." Additionally, "Expression of MKS3 was
      up-regulated by genetic or pharmacological inducers of ER stress." This
      represents a secondary localization relevant to the ERAD function of TMEM67.
    action: KEEP_AS_NON_CORE
    reason: >-
      The ER membrane localization is experimentally demonstrated (IDA) and relevant
      to the ERAD adaptor function of TMEM67. However, the primary localization of
      TMEM67 is the ciliary transition zone. The ER localization may reflect a
      fraction of the protein pool involved in ERAD. This is a valid but non-core
      localization.
    supported_by:
      - reference_id: PMID:19815549
        supporting_text: >-
          MKS3 was identified as a membrane glycoprotein predominantly localized to
          the ER.
      - reference_id: PMID:19815549
        supporting_text: >-
          Expression of MKS3 was up-regulated by genetic or pharmacological inducers
          of ER stress.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:17185389
  review:
    summary: >-
      IDA annotation for centrosome localization from PMID:17185389 (Dawe et al.
      2007). The UniProt record lists "Cytoplasm, cytoskeleton, cilium basal body"
      as a subcellular location. The paper described MKS1 localization to basal
      bodies and meckelin localization to the cilium and plasma membrane. The
      centrosome/basal body localization is relevant to TMEM67 role in centrosome
      migration to the apical cell surface during ciliogenesis. PMID:22121117
      also confirmed basal body localization.
    action: ACCEPT
    reason: >-
      Centrosome/basal body localization is relevant to the core function of TMEM67
      in centriole migration to the apical membrane during ciliogenesis. The basal
      body is a modified centrosome, and TMEM67 localization there is consistent with
      its role in ciliogenesis.
    supported_by:
      - reference_id: PMID:17185389
        supporting_text: >-
          siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated
          epithelial cell-line blocked centriole migration to the apical membrane
          and consequent formation of the primary cilium.
      - reference_id: PMID:22121117
        supporting_text: >-
          the cytoplasmic domain of meckelin directly interacts with the
          actin-binding protein filamin A, potentially at the apical cell surface
          associated with the basal body.
- term:
    id: GO:0010826
    label: negative regulation of centrosome duplication
  evidence_type: IMP
  original_reference_id: PMID:19515853
  review:
    summary: >-
      IMP annotation for negative regulation of centrosome duplication from
      PMID:19515853 (Tammachote et al. 2009). The paper showed that in wpk (Mks3
      mutant) rat renal collecting duct cysts, there was "additional evidence of
      cells with multiple primary cilia and centrosome over-duplication." Stable
      shRNA knockdown of Mks3 "induced multi-ciliated and multi-centrosomal
      phenotypes." The paper concluded that "MKS1 and MKS3 functions are required
      for ciliary structure and function, including a role in regulating length and
      appropriate number through modulating centrosome duplication."
    action: ACCEPT
    reason: >-
      The negative regulation of centrosome duplication is well supported by the
      mutant phenotype data in PMID:19515853, showing centrosome over-duplication
      in Mks3 mutant and knockdown cells. This is a specific and informative
      biological process annotation directly relevant to TMEM67 function in
      ciliogenesis.
    supported_by:
      - reference_id: PMID:19515853
        supporting_text: >-
          In wpk renal collecting duct cysts, cilia were generally longer than
          normal, with additional evidence of cells with multiple primary cilia and
          centrosome over-duplication.
      - reference_id: PMID:19515853
        supporting_text: >-
          Stable shRNA knockdown of Mks1 and Mks3 in IMCD3 cells induced
          multi-ciliated and multi-centrosomal phenotypes.
      - reference_id: PMID:19515853
        supporting_text: >-
          MKS1 and MKS3 functions are required for ciliary structure and function,
          including a role in regulating length and appropriate number through
          modulating centrosome duplication.
- term:
    id: GO:0030659
    label: cytoplasmic vesicle membrane
  evidence_type: IDA
  original_reference_id: PMID:19815549
  review:
    summary: >-
      IDA annotation for cytoplasmic vesicle membrane localization from
      PMID:19815549 (Wang et al. 2009). The paper studied TMEM67 in the context
      of ERAD and identified it as an ER membrane glycoprotein. The cytoplasmic
      vesicle membrane localization may reflect ER-derived vesicular structures
      or experimental observation of TMEM67 in vesicular compartments. This is
      a minor, secondary localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a secondary localization observed in the context of the ERAD study.
      While the IDA evidence supports this localization, it is not a primary or core
      localization for TMEM67. The main localizations are the ciliary transition zone
      and ER membrane.
    supported_by:
      - reference_id: PMID:19815549
        supporting_text: >-
          MKS3 was identified as a membrane glycoprotein predominantly localized to
          the ER.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:19815549
  review:
    summary: >-
      IMP annotation for ERAD pathway involvement from PMID:19815549 (Wang et al.
      2009). The paper demonstrated that "Microarray screens for genes involved in
      SP-C ER-associated degradation identified MKS3/TMEM67." Further, "knockdown
      of MKS3 also inhibited degradation of mutant SP-C" and "Deletion of the
      transmembrane and cytosolic domains abrogated interaction of MKS3 with p97
      and resulted in accumulation of mutant SP-C proprotein." TMEM67 functions as
      an adaptor linking the ER lumenal quality control machinery with the cytosolic
      degradation apparatus (p97/VCP).
    action: KEEP_AS_NON_CORE
    reason: >-
      The ERAD pathway involvement is well supported by experimental evidence
      showing that TMEM67 loss inhibits degradation of misfolded surfactant
      protein C. However, this is a secondary, non-core function of TMEM67.
      Its primary roles are at the ciliary transition zone in ciliogenesis and
      non-canonical Wnt signaling. The ERAD role appears to be specific to
      misfolded SP-C processing and may not represent a general function.
    supported_by:
      - reference_id: PMID:19815549
        supporting_text: >-
          Microarray screens for genes involved in SP-C ER-associated degradation
          identified MKS3/TMEM67, a locus previously linked to the ciliopathy
          Meckel-Gruber syndrome.
      - reference_id: PMID:19815549
        supporting_text: >-
          knockdown of MKS3 also inhibited degradation of mutant SP-C.
      - reference_id: PMID:19815549
        supporting_text: >-
          These results support a model in which MKS3 links the ER lumenal quality
          control machinery with the cytosolic degradation apparatus.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IPI
  original_reference_id: PMID:19815549
  review:
    summary: >-
      This annotation to GO:0051082 (unfolded protein binding) is based on
      PMID:19815549 (Wang et al. 2009), which studied the role of MKS3/TMEM67
      in ERAD of misfolded surfactant protein C (SP-C). The WITH/FROM field
      indicates UniProtKB:P11686 (SFTPC). The paper demonstrated that the ER
      lumenal domain of MKS3 interacted with a complex that included mutant
      SP-C and associated chaperones (ERdj4/DNAJB9 and ERdj5/DNAJC10), and
      that the transmembrane domains of MKS3 interacted with cytosolic p97.
      However, MKS3 is not a chaperone. The authors concluded that MKS3
      functions as an adaptor that links the ER lumenal quality control
      machinery with the cytosolic degradation apparatus, rather than directly
      binding unfolded protein in a chaperone-like manner. The interaction
      with misfolded SP-C appears to be indirect, mediated through association
      with the chaperone complex. TMEM67 is a multi-pass transmembrane protein
      of the ciliary transition zone with no known chaperone domains. The term
      GO:0051082 is also being obsoleted (go-ontology issue 30962) because it
      conflates passive binding with active chaperone functions. This annotation
      represents an over-annotation where an adaptor role in ERAD was
      inappropriately classified as unfolded protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      TMEM67/MKS3 is not a chaperone and does not possess intrinsic unfolded
      protein binding activity. The evidence in PMID:19815549 shows that MKS3
      interacts with a complex containing misfolded SP-C and bona fide ER
      chaperones, but functions as an adaptor linking the ER lumenal quality
      control machinery with the cytosolic degradation apparatus (p97), not
      as a chaperone itself. The annotation to GO:0036503 (ERAD pathway)
      already appropriately captures the biological process role. The molecular
      function of TMEM67 in this context is better described as an adaptor or
      scaffold linking chaperone-substrate complexes to the retrotranslocation
      machinery, not as direct unfolded protein binding. Furthermore,
      GO:0051082 is being obsoleted (go-ontology issue 30962) as it conflates
      passive binding with active chaperone activity.
    supported_by:
      - reference_id: PMID:19815549
        supporting_text: >-
          These results support a model in which MKS3 links
          the ER lumenal quality control machinery with the cytosolic degradation
          apparatus.
      - reference_id: PMID:19815549
        supporting_text: >-
          The ER lumenal
          domain of MKS3 interacted with a complex that included mutant SP-C and
          associated chaperones, whereas the region predicted to encode the transmembrane
          domains of MKS3 interacted with cytosolic p97.
      - reference_id: PMID:19815549
        supporting_text: >-
          Deletion of the transmembrane and
          cytosolic domains abrogated interaction of MKS3 with p97 and resulted in
          accumulation of mutant SP-C proprotein; knockdown of MKS3 also inhibited
          degradation of mutant SP-C.
      - reference_id: PMID:19815549
        supporting_text: >-
          Microarray screens for genes involved in SP-C
          ER-associated degradation identified MKS3/TMEM67, a locus previously linked to
          the ciliopathy Meckel-Gruber syndrome.
- term:
    id: GO:0060170
    label: ciliary membrane
  evidence_type: IDA
  original_reference_id: PMID:17185389
  review:
    summary: >-
      IDA annotation for ciliary membrane localization from PMID:17185389 (Dawe
      et al. 2007). The paper demonstrated that "meckelin localized both to the
      primary cilium and to the plasma membrane in ciliated cell-lines and primary
      cells." As a multi-pass transmembrane protein, TMEM67 is embedded in the
      ciliary membrane at the transition zone region.
    action: ACCEPT
    reason: >-
      Ciliary membrane localization is directly demonstrated by immunofluorescence
      in PMID:17185389. TMEM67 is a transmembrane protein spanning the ciliary
      membrane at the transition zone. This is consistent with the transition zone
      localization and represents a core subcellular localization.
    supported_by:
      - reference_id: PMID:17185389
        supporting_text: >-
          meckelin localized both to the primary cilium and to the plasma membrane
          in ciliated cell-lines and primary cells.
- term:
    id: GO:0060271
    label: cilium assembly
  evidence_type: IMP
  original_reference_id: PMID:19515853
  review:
    summary: >-
      IMP annotation for cilium assembly from PMID:19515853 (Tammachote et al.
      2009). The paper showed functional defects in the connecting cilium in the
      eye of wpk (Mks3 mutant) rats, "lack of formation of the outer segment,"
      and "spermatids with very short flagella." Stable shRNA knockdown of Mks3
      "induced multi-ciliated and multi-centrosomal phenotypes." The paper
      concluded that "MKS1 and MKS3 functions are required for ciliary structure
      and function."
    action: ACCEPT
    reason: >-
      This IMP annotation provides direct experimental evidence from mutant
      phenotype analysis supporting the core role of TMEM67 in cilium assembly.
      The data complement the earlier knockdown studies in PMID:17185389 and
      the IBA annotation.
    supported_by:
      - reference_id: PMID:19515853
        supporting_text: >-
          Analysis of the wpk rat model of MKS3 revealed functional defects of the
          connecting cilium in the eye that resulted in lack of formation of the
          outer segment, whereas infertile wpk males developed spermatids with very
          short flagella that did not extend beyond the cell body.
      - reference_id: PMID:19515853
        supporting_text: >-
          MKS1 and MKS3 functions are required for ciliary structure and function,
          including a role in regulating length and appropriate number through
          modulating centrosome duplication.
- term:
    id: GO:0017147
    label: Wnt-protein binding
  evidence_type: IPI
  original_reference_id: PMID:26035863
  review:
    summary: >-
      NEW annotation. PMID:26035863 demonstrated that the extracellular N-terminal
      domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay.
      PMID:34731008 confirmed this interaction structurally. The existing protein
      binding annotations with WNT5A (PMID:34731008) and ROR2 (PMID:26035863)
      should be replaced by this more specific term.
    action: NEW
    reason: >-
      TMEM67 directly binds WNT5A via its extracellular cysteine-rich domain, a
      core molecular function for this protein. The Wnt-protein binding term is
      significantly more informative than generic protein binding and captures a
      key functional attribute of TMEM67 as a non-canonical Wnt receptor.
    supported_by:
      - reference_id: PMID:26035863
        supporting_text: >-
          the extracellular N-terminal domain of TMEM67 preferentially binds to
          Wnt5a in an in vitro binding assay.
      - reference_id: PMID:34731008
        supporting_text: >-
          Recently, it has been suggested that Meckelin can function as a receptor
          of β-catenin–independent signaling that binds to Wnt5a and mediates
          downstream signaling through receptor tyrosine kinase-like orphan
          receptor 2 as a coreceptor, thereby controlling basal body positioning
          and epithelial branching morphogenesis (12).
    additional_reference_ids:
      - PMID:34731008
core_functions:
- molecular_function:
    id: GO:0017147
    label: Wnt-protein binding
  description: >-
    TMEM67 (meckelin) acts as a receptor for non-canonical Wnt signaling by directly
    binding WNT5A through its extracellular cysteine-rich domain (CRD), which is
    homologous to Frizzled/ROR receptors. It cooperates with ROR2 as a co-receptor
    to mediate non-canonical Wnt signaling that controls basal body positioning and
    epithelial branching morphogenesis. TMEM67 is essential for phosphorylation of
    ROR2 upon WNT5A stimulation. Recent work (DOI:10.1101/2024.09.04.611229) shows
    that ADAMTS9 proteolytic cleavage of TMEM67 generates a functional partition:
    the released N-terminal ectodomain is proposed to modulate Wnt signaling, while
    the C-terminal fragment supports TZ assembly. Cleavage-deficient TMEM67 mice
    retain apparently normal Wnt signaling while showing severe ciliogenesis/TZ
    phenotypes, supporting mechanistic separability of Wnt-related and TZ-related
    functions.
  directly_involved_in:
    - id: GO:0035567
      label: non-canonical Wnt signaling pathway
    - id: GO:0060271
      label: cilium assembly
  locations:
    - id: GO:0035869
      label: ciliary transition zone
    - id: GO:0060170
      label: ciliary membrane
  in_complex:
    id: GO:0036038
    label: MKS complex
  supported_by:
    - reference_id: PMID:26035863
      supporting_text: >-
        We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt
        signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling.
    - reference_id: PMID:26035863
      supporting_text: >-
        the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in
        an in vitro binding assay.
    - reference_id: PMID:34731008
      supporting_text: >-
        Recently, it has been suggested that Meckelin can function as a receptor of
        beta-catenin-independent signaling that binds to Wnt5a and mediates downstream
        signaling through receptor tyrosine kinase-like orphan receptor 2 as a coreceptor.
- molecular_function:
    id: GO:0031005
    label: filamin binding
  description: >-
    The cytoplasmic domain of TMEM67 directly interacts with filamin A (FLNA) at the
    apical cell surface associated with the basal body. This interaction mediates
    ciliogenesis and basal body positioning. Loss of filamin A phenocopies meckelin loss,
    causing basal body positioning and ciliogenesis defects. TMEM67 is positioned as a
    central organizer within MKS-related TZ assemblies: loss of TMEM67 or its ADAMTS9-
    mediated cleavage causes reduced recruitment of multiple MKS/B9 module proteins
    (TCTN1/2/3, TMEM237, CC2D2A, B9D2) to mature basal bodies/TZ, and disruption of the
    TZ necklace ultrastructure (DOI:10.1101/2024.09.04.611229).
  directly_involved_in:
    - id: GO:0060271
      label: cilium assembly
    - id: GO:0010826
      label: negative regulation of centrosome duplication
    - id: GO:1904491
      label: protein localization to ciliary transition zone
  locations:
    - id: GO:0035869
      label: ciliary transition zone
    - id: GO:0005813
      label: centrosome
  in_complex:
    id: GO:0036038
    label: MKS complex
  supported_by:
    - reference_id: PMID:22121117
      supporting_text: >-
        the cytoplasmic domain of meckelin directly interacts with the actin-binding
        protein filamin A, potentially at the apical cell surface associated with the
        basal body.
    - reference_id: PMID:22121117
      supporting_text: >-
        loss of filamin A by siRNA knockdown, in patient cells, and in tissues from
        Flna(Dilp2) null mouse embryos results in cellular phenotypes identical to
        those caused by meckelin loss, namely basal body positioning and ciliogenesis
        defects.
    - reference_id: PMID:19515853
      supporting_text: >-
        MKS1 and MKS3 functions are required for ciliary structure and function,
        including a role in regulating length and appropriate number through modulating
        centrosome duplication.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:17185389
  title: The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required
    for primary cilium formation.
  findings: []
- id: PMID:19515853
  title: Ciliary and centrosomal defects associated with mutation and depletion of
    the Meckel syndrome genes MKS1 and MKS3.
  findings: []
- id: PMID:19815549
  title: Meckel-Gruber syndrome protein MKS3 is required for endoplasmic reticulum-associated
    degradation of surfactant protein C.
  findings: []
- id: PMID:22121117
  title: A meckelin-filamin A interaction mediates ciliogenesis.
  findings: []
- id: PMID:22179047
  title: A ciliopathy complex at the transition zone protects the cilia as a privileged
    membrane domain.
  findings: []
- id: PMID:26035863
  title: The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning
    and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway.
  findings: []
- id: PMID:26595381
  title: TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition
    zone and causes Joubert syndrome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:34731008
  title: Structure of the human Meckel-Gruber protein Meckelin.
  findings: []
- id: PMID:34964473
  title: Interpreting ciliopathy-associated missense variants of uncertain significance
    (VUS) in Caenorhabditis elegans.
  findings: []
- id: PMID:35137054
  title: The ciliary transition zone protein TMEM218 synergistically interacts with
    the NPHP module and its reduced dosage leads to a wide range of syndromic ciliopathies.
  findings: []
- id: Reactome:R-HSA-5617816
  title: RAB3IP stimulates nucleotide exchange on RAB8A
  findings: []
- id: Reactome:R-HSA-5626681
  title: Recruitment of transition zone proteins
  findings: []
- id: Reactome:R-HSA-5638009
  title: CEP164 recruits RAB3IP-carrying Golgi-derived vesicles to the basal body
  findings: []
- id: DOI:10.1101/2024.09.04.611229
  title: Two functional forms of the Meckel-Gruber syndrome protein TMEM67 generated
    by proteolytic cleavage by ADAMTS9 mediate Wnt signaling and ciliogenesis
  findings:
    - statement: >-
        TMEM67 is a proteolytic substrate of the metalloproteinase ADAMTS9,
        generating two functional forms: a released N-terminal ectodomain fragment
        proposed to modulate Wnt signaling and a C-terminal fragment (Delta342)
        that localizes to the TZ and supports ciliogenesis/TZ assembly.
    - statement: >-
        Loss of TMEM67 or ADAMTS9 causes reduced recruitment of multiple MKS/B9
        module proteins (TCTN1/2/3, TMEM237, CC2D2A, B9D2) to mature basal
        bodies/TZ, positioning TMEM67 as a central organizer within MKS-related
        TZ assemblies.
    - statement: >-
        Cleavage-deficient (non-cleavable) TMEM67 mice retain apparently normal
        Wnt signaling but show severe ciliogenesis/TZ phenotypes including loss of
        the TZ necklace formation, supporting mechanistic separability of
        Wnt-related and TZ-related TMEM67 functions.
    - statement: >-
        TMEM67 is the most commonly mutated gene in MKS, accounting for
        approximately 16-20% of MKS cases.
    - statement: >-
        Patient variants near the TMEM67 cleavage motif (e.g., p.K329T, p.F342V,
        p.L349S) fail to rescue ciliogenesis/TZ localization in TMEM67 knockout
        cells and produce strong loss-of-function phenotypes in C. elegans MKS-3
        assays, supporting clinical significance of this extracellular region.
- id: DOI:10.54029/2024wir
  title: Joubert syndrome caused by a TMEM67 mutation - genotype-phenotype analysis
  findings:
    - statement: >-
        TMEM67 pathogenic variants contribute to around 80% of Joubert
        syndrome-related disorders characterized by liver involvement, with
        mutational hotspots including exon 8.
- id: DOI:10.3389/fneph.2023.1331847
  title: Primary cilia and actin regulatory pathways in renal ciliopathies
  findings:
    - statement: >-
        The primary cilium functions as a cellular antenna for transducing
        extracellular signals that regulate development and tissue homeostasis;
        the transition zone acts as a diffusion/trafficking barrier regulating the
        protein/lipid composition of the ciliary membrane and axoneme.
- id: DOI:10.1038/s41598-017-01519-4
  title: An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated
    with dysmorphic primary cilia and TMEM67 mutations
  findings:
    - statement: >-
        In the ovine TMEM67-associated Meckel-like hepatorenal model, cultured
        kidney interstitial fibroblasts showed significantly increased primary
        cilium length in affected animals versus controls (15.1 vs 8.3 micrometers),
        while ciliation incidence was similar.
- id: DOI:10.1038/s41431-022-01267-8
  title: Challenges for the implementation of next generation sequencing-based expanded
    carrier screening - lessons learned from the ciliopathies
  findings:
    - statement: >-
        In a carrier screening study of 395 healthy individuals across 118
        ciliopathy genes, approximately 11% carried a pathogenic variant, and 50%
        carried 1-5 strong VUS, highlighting high VUS rates and the need for
        gene-specific variant interpretation in ciliopathy diagnostics.