Affinage

TMEM138

Transmembrane protein 138 · UniProt Q9NPI0

Length
162 aa
Mass
19.3 kDa
Annotated
2026-06-10
16 papers in source corpus 4 papers cited in narrative 4 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM138 is a transmembrane protein of the ciliary transition zone that governs the trafficking of ciliary membrane cargo and the biogenesis of the photoreceptor outer segment (PMID:22282472, PMID:35394880). Its localization to the transition zone depends on CEP-290, and it occupies a distinct CEP-290-associated module separate from the canonical MKS and NPHP modules, showing no interdependent localization with their core components (PMID:26982032). In photoreceptors, TMEM138 localizes to the connecting cilium where it physically interacts with rhodopsin and with TMEM231 and is required for delivery of rhodopsin to the outer segment, for positioning AHI1 and TMEM231 within the connecting cilium, and for outer segment morphogenesis and disc renewal (PMID:35394880, PMID:41747882). The gene is encoded in a head-to-tail configuration with the neighboring TMEM216 and shares a conserved intergenic cis-regulatory element, coupling the two genes in an interdependent role in vesicular transport to primary cilia; loss-of-function mutation of either gene causes a phenotypically indistinguishable Joubert syndrome ciliopathy (PMID:22282472).

Mechanistic history

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

    Established TMEM138 as a ciliopathy gene and revealed it is genomically and regulatorily coupled to TMEM216, defining a shared role in vesicular transport to the primary cilium.

    Evidence Human mutation identification, comparative synteny analysis, reporter assays for the shared cis-regulatory element, and cellular vesicular-transport assays

    PMID:22282472

    Open questions at the time
    • Did not define the molecular activity of TMEM138 at the cilium
    • Mechanism by which the two genes act interdependently in vesicular transport was not resolved
  2. 2016 High

    Placed TMEM138 within the transition-zone architecture by showing its localization is CEP-290-dependent yet independent of the MKS and NPHP modules, defining a distinct module.

    Evidence Genetic epistasis and interdependent localization assays with immunofluorescence in C. elegans cep-290 and module-component mutants

    PMID:26982032

    Open questions at the time
    • Did not identify direct binding partners of TMEM138 in the module
    • How CEP-290 recruits TMEM138 was not determined
  3. 2022 High

    Defined TMEM138's photoreceptor function and direct partners, linking it to rhodopsin trafficking, connecting-cilium organization, and outer segment biogenesis.

    Evidence Germline and rod-specific Tmem138 knockout mice with immunofluorescence/fractionation, reciprocal co-IP for rhodopsin and TMEM231, and electron microscopy of outer segments

    PMID:35394880

    Open questions at the time
    • Whether the rhodopsin and TMEM231 interactions are direct or bridged was not resolved
    • Structural basis of cargo selectivity unknown
  4. 2026 Medium

    Provided direct functional confirmation that TMEM138 supports ongoing photoreceptor disc turnover, not merely initial morphogenesis.

    Evidence AAV-delivered photoconvertible Dendra2-rhodopsin renewal assay in Tmem138 knockout mice with quantitative comparison of renewal length

    PMID:41747882

    Open questions at the time
    • Single-lab measurement with one method for the renewal readout
    • Does not establish the step in renewal that TMEM138 controls

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical activity of TMEM138 as a transmembrane protein and the mechanism by which it mediates cargo transport to the cilium remain undefined.
  • No enzymatic or transport activity assigned
  • No structural model of TMEM138 or its complexes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005929 cilium 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
AHI1CEP290RHOTMEM216TMEM231

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Mutation of either TMEM138 or TMEM216 causes phenotypically indistinguishable Joubert syndrome ciliopathy; the two genes are arranged in a head-to-tail configuration joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition, share a conserved cis-regulatory element in their intergenic region, and have an interdependent cellular role in vesicular transport to primary cilia. Human genetics (mutation identification), comparative genomics (synteny analysis), reporter assays for shared regulatory element, cell biological assays for vesicular transport to cilia Science (New York, N.Y.) High 22282472
2016 In C. elegans, TZ localization of TMEM-138 (Tmem138 orthologue) depends on CEP-290; however, TMEM-138 does not exhibit interdependent localization or genetic interactions with core MKS or NPHP module components, placing it in a distinct, CEP-290-associated TZ module separate from the canonical MKS and NPHP modules. Genetic epistasis in C. elegans (interdependent localization assays, double-mutant analysis), immunofluorescence of TZ proteins in cep-290 mutants PLoS biology High 26982032
2022 Mouse Tmem138 localizes to the photoreceptor connecting cilium (CC), is required for localization of Ahi1 to the distal subdomain of the CC, is essential for rhodopsin localization (rhodopsin mislocalizes throughout the cell body before outer segment morphogenesis in knockouts), and is required for outer segment biogenesis and disc renewal; Tmem138 physically interacts (reciprocal co-IP) with rhodopsin and with Tmem231, and the ciliary localization of Tmem231 is altered in Tmem138 mutant photoreceptors. Germline and conditional (rod-specific) Tmem138 knockout mice; immunofluorescence/fractionation for protein localization; reciprocal co-immunoprecipitation for Tmem138–rhodopsin and Tmem138–Tmem231 interactions; electron microscopy of outer segment structure 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 directly measured by AAV-delivered photoconvertible Rhodopsin/Dendra2, confirming a functional role of Tmem138 in photoreceptor disc turnover. AAV-delivered Dendra2-tagged rhodopsin photoconversion assay in Tmem138 knockout mice; quantitative comparison of OS renewal lengths at two time points 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.) 229 29025994
2016 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone. PLoS biology 110 26982032
2017 Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. Journal of medical genetics 87 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 60 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 12 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 6 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

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