Affinage

TMEM138

Transmembrane protein 138 · UniProt Q9NPI0

Length
162 aa
Mass
19.3 kDa
Annotated
2026-04-28
16 papers in source corpus 4 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM138 is a ciliary transition zone transmembrane protein that functions in vesicular transport to primary cilia and is essential for outer segment morphogenesis and disc renewal in photoreceptors. It localizes to the transition zone in a CEP290-dependent manner as part of a distinct module separate from the core MKS and NPHP complexes, and it physically interacts with rhodopsin and Tmem231 to mediate rhodopsin trafficking and proper ciliary protein localization (PMID:26982032, PMID:35394880). TMEM138 is co-regulated with TMEM216 via a shared cis-regulatory element, and their coordinated expression is required for their interdependent roles in ciliogenesis; loss-of-function mutations in TMEM138 cause Joubert syndrome (PMID:22282472). In photoreceptors, Tmem138 deletion abolishes outer segment biogenesis, disrupts Ahi1 localization to the connecting cilium distal subdomain, and reduces disc renewal rate, leading to rapid photoreceptor degeneration (PMID:35394880, PMID:41747882).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2012 High

    Establishing that TMEM138 is a ciliary gene with a role in vesicular transport to primary cilia resolved its basic cellular function and linked it to Joubert syndrome, a ciliopathy previously associated with its genomic neighbor TMEM216.

    Evidence Chromosomal synteny analysis, cis-regulatory element identification, and vesicular transport assays in mammalian cells

    PMID:22282472

    Open questions at the time
    • Precise molecular cargo carried during vesicular transport not identified
    • No structural information on TMEM138 or its interaction with TMEM216
    • Mechanism by which shared regulatory element coordinates expression unknown
  2. 2016 High

    Placing TMEM138 in a CEP290-dependent but MKS/NPHP-independent module at the transition zone clarified its hierarchical position within the ciliary gate protein network.

    Evidence Genetic epistasis and interdependent localization hierarchy in C. elegans, complemented by patient fibroblast ciliogenesis assays

    PMID:26982032

    Open questions at the time
    • Identity of other components in the CEP290-associated module beyond TMEM138 incompletely defined
    • Whether the CEP290-dependent localization mechanism is conserved in vertebrates not directly tested
    • Direct biochemical interaction between TMEM138 and CEP290 not demonstrated
  3. 2022 High

    Demonstrating that Tmem138 physically interacts with rhodopsin and Tmem231 and is required for rhodopsin trafficking, Ahi1 localization, and outer segment morphogenesis provided a concrete molecular mechanism for its ciliary transport function in photoreceptors.

    Evidence Germline and conditional rod-specific knockout mice, reciprocal co-immunoprecipitation, immunofluorescence, and subcellular fractionation

    PMID:35394880

    Open questions at the time
    • Whether TMEM138 directly binds rhodopsin or requires bridging factors is unclear
    • How Tmem138 loss disrupts Ahi1 localization mechanistically is not resolved
    • No structure-function analysis of TMEM138 domains
  4. 2026 Medium

    Quantifying reduced outer segment disc renewal rate in Tmem138-deficient photoreceptors confirmed its ongoing role in disc dynamics beyond initial OS morphogenesis.

    Evidence AAV-delivered Dendra2-tagged rhodopsin photoconversion assay in Tmem138-knockout mice

    PMID:41747882

    Open questions at the time
    • Single study using one quantitative readout; independent replication pending
    • Whether reduced renewal reflects a trafficking defect, disc assembly defect, or both is unresolved
    • Contribution of TMEM138 to disc renewal in cones not examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of TMEM138 function, identification of its full interactome at the transition zone, and whether its vesicular transport role operates through the same mechanism in photoreceptors and other ciliated cell types.
  • No structural or atomic-resolution model of TMEM138
  • Full composition of the CEP290-associated module unknown
  • Mechanism linking TMEM138 to vesicle docking or fusion at the ciliary base undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005929 cilium 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
AHI1CEP290RHOTMEM216TMEM231

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 TMEM138 and TMEM216 are aligned in a head-to-tail configuration joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition; expression of both genes is mediated by a conserved regulatory element in the noncoding intergenic region, and their coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Mutation of either gene causes phenotypically indistinguishable Joubert syndrome ciliopathy. Genetic mapping, chromosomal synteny analysis, cis-regulatory element identification, functional studies of vesicular transport to primary cilia Science (New York, N.Y.) High 22282472
2016 In C. elegans, TMEM-138 (Tmem138 ortholog) localizes to the ciliary transition zone in a CEP-290-dependent manner but does not show interdependent localization or genetic interactions with core MKS or NPHP module components, suggesting it belongs to a distinct CEP-290-associated module. Pathogenic mutations in Tmem138 are associated with Oral-Facial-Digital syndrome type 6 (OFD6). Epistasis analysis, interdependent protein localization hierarchy in C. elegans, patient fibroblast ciliogenesis assays PLoS biology High 26982032
2022 Tmem138 localizes to the photoreceptor connecting cilium (CC) and is required for: (1) rhodopsin localization prior to outer segment (OS) morphogenesis, (2) Ahi1 localization to the distal subdomain of the CC, and (3) OS biogenesis and disc renewal. Tmem138 physically interacts (reciprocal co-immunoprecipitation) with rhodopsin and Tmem231, and loss of Tmem138 alters ciliary localization of Tmem231. Germline or conditional rod-specific deletion abolishes OS morphogenesis and causes rapid photoreceptor degeneration. Germline and conditional knockout mouse, reciprocal Co-IP, immunofluorescence localization, subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America High 35394880
2026 Tmem138-deficient mice exhibit a reduced outer segment renewal rate, as measured by AAV-delivered photoconvertible Rhodopsin/Dendra2, confirming Tmem138's functional role in disc renewal dynamics in mature photoreceptors. AAV-delivered Dendra2-tagged rhodopsin photoconversion assay in Tmem138-knockout mice Experimental eye research Medium 41747882

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Loci associated with skin pigmentation identified in African populations. Science (New York, N.Y.) 227 29025994
2016 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone. PLoS biology 108 26982032
2017 Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. Journal of medical genetics 85 28289185
2012 Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. Science (New York, N.Y.) 71 22282472
2019 Single-Locus and Multi-Locus Genome-Wide Association Studies for Intramuscular Fat in Duroc Pigs. Frontiers in genetics 59 31316554
2016 Molecular genetic analysis of 30 families with Joubert syndrome. Clinical genetics 44 27434533
2022 Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis. Proceedings of the National Academy of Sciences of the United States of America 21 35394880
2024 Skin colour: A window into human phenotypic evolution and environmental adaptation. Molecular ecology 10 38713101
2021 Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy. Frontiers in pharmacology 8 34899357
2021 Meckel Gruber and Joubert Syndrome Diagnosed Prenatally: Allelism between the Two Ciliopathies, Complexities of Mutation Types and Digenic Inheritance. Fetal and pediatric pathology 5 34821546
2021 The diagnostic yield of whole exome sequencing as a first approach in consanguineous Omani renal ciliopathy syndrome patients. F1000Research 4 34354814
2012 Basal vertebrates clarify the evolutionary history of ciliopathy-associated genes Tmem138 and Tmem216. Molecular biology and evolution 4 22936720
2023 Molecular characteristics and transcriptional regulatory of spermatogenesis-related gene RFX2 in adult Banna mini-pig inbred line (BMI). Animal reproduction 2 36922987
2026 Comparison of rod photoreceptor outer segment renewal in wild type and Tmem138-deficient mice using AAV-delivered Dendra2-tagged rhodopsin. Experimental eye research 0 41747882
2025 TMEM138: From Biological Functions to Diseases. Physiological research 0 40432436
2025 Visualization of photoreceptor outer segment renewal using AAV-delivered Dendra2-tagged rhodopsin. bioRxiv : the preprint server for biology 0 41409134