Affinage

TMEM231

Transmembrane protein 231 · UniProt Q9H6L2

Length
316 aa
Mass
36.1 kDa
Annotated
2026-06-10
21 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM231 is a two-pass transmembrane component of the ciliary transition zone (TZ) that helps establish and maintain the membrane diffusion barrier separating the ciliary compartment from the rest of the cell (PMID:22179047, PMID:25869670). It is recruited to the TZ before and independently of intraflagellar transport, in a Septin2-regulated manner, and assembles into the MKS module through mutual localization dependencies with B9D1, CC2D2A, and MKS1 (PMID:22179047, PMID:25869670); in C. elegans this targeting is organized by TMEM-107 and lies hierarchically downstream of the MKS-5 (Rpgrip1L)/CEP-290 assembly pathway, with the protein behaving as an immobile structural element of the TZ scaffold (PMID:26595381, PMID:26982032). Functionally, TMEM231 restricts entry and exit of membrane proteins at the TZ and is required for correct ciliary localization of the signaling regulators Arl13b and Inpp5e, and its loss causes reduced ciliogenesis, mislocalization of ciliary receptors, and defective Sonic Hedgehog pathway activation that manifests in mouse as polydactyly, kidney cysts, and midfacial defects rescuable by lowering Ptch1 dosage (PMID:22179047, PMID:25869670, PMID:34672258). TMEM231 also interacts reciprocally with TMEM138 — which is required for its proper localization at the connecting cilium — and with caveolin-1 (PMID:35394880, PMID:37997673). Loss-of-function splice variants abolish primary cilia in human kidney tissue and cause Meckel-Gruber syndrome (PMID:37736303).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 High

    Established that TMEM231 is not a passive ciliary resident but a functional subunit of a TZ diffusion-barrier complex controlling what enters and exits the cilium.

    Evidence RNAi screening, proteomics, mouse knockouts, and ciliary diffusion-rate assays in mammalian cells

    PMID:22179047

    Open questions at the time
    • Molecular nature of the diffusion barrier (lipid vs protein gate) not resolved
    • Direct biochemical contacts within the complex not mapped at residue level
  2. 2015 High

    Defined TMEM231 as essential for MKS complex organization and for ciliary delivery of specific signaling proteins, with conservation from mouse to C. elegans.

    Evidence Tmem231 mouse knockout, C. elegans genetics, immunofluorescence, and patient-mutation functional validation

    PMID:25869670

    Open questions at the time
    • Mechanism by which TMEM231 gates Arl13b/Inpp5e entry not defined
    • Whether mislocalization is direct or secondary to barrier collapse unresolved
  3. 2015 High

    Placed TMEM231 within a layered TZ architecture, recruited by TMEM-107 and behaving as an immobile scaffold element rather than a dynamic transporter.

    Evidence C. elegans tmem-107 mutants, super-resolution microscopy, and FRAP of MKS module proteins

    PMID:26595381

    Open questions at the time
    • Mammalian equivalence of the TMEM-107 recruitment step not directly tested here
    • Stoichiometry and periodicity of the scaffold not quantified at molecular resolution
  4. 2016 High

    Positioned TMEM231 TZ targeting hierarchically downstream of CEP-290 and MKS-5, defining its place in the assembly order.

    Evidence C. elegans cep-290 and mks-5 mutant epistasis with TMEM-231 localization tracking

    PMID:26982032

    Open questions at the time
    • Direct physical link between CEP-290/MKS-5 and TMEM231 not demonstrated
    • Conservation of the hierarchy in vertebrates not established in this study
  5. 2021 High

    Connected TMEM231 loss to a tissue-level developmental phenotype through defective Hedgehog activation, with genetic rescue confirming it acts upstream of the pathway.

    Evidence Mouse Tmem231; Ptch1 double-mutant epistasis, HH pathway markers, and TUNEL cell-death assays

    PMID:34672258

    Open questions at the time
    • How TZ barrier integrity translates into HH signal output not mechanistically dissected
    • Whether the same mechanism drives polydactyly and kidney phenotypes not addressed
  6. 2022 Medium

    Identified TMEM138 as a reciprocal physical partner required for correct TMEM231 localization at the connecting cilium, extending the interaction network.

    Evidence Reciprocal Co-IP and Tmem138 germline knockout with TMEM231 mislocalization in photoreceptors

    PMID:35394880

    Open questions at the time
    • Single-lab finding without independent confirmation
    • Direct vs indirect nature of the TMEM138 dependency not separated
  7. 2023 Medium

    Confirmed in human tissue that TMEM231 loss-of-function abolishes primary cilia, directly linking the molecular defect to ciliopathy pathology.

    Evidence cDNA cloning and RT-PCR of splice variants plus immunofluorescence of primary cilia in patient kidney tissue (Meckel Syndrome fetus)

    PMID:37736303

    Open questions at the time
    • Mechanistic step from mRNA loss to cilia absence not dissected
    • Limited to a single patient sample
  8. 2023 Low

    Proposed that caveolin-1 and lipid-raft association contribute to TMEM231 retention at the TZ, with galectin-8-induced cilium elongation redistributing it into the axoneme.

    Evidence Co-IP of caveolin-1 with TMEM231, imaging of redistribution upon galectin-8, and pharmacological raft disruption

    PMID:37997673

    Open questions at the time
    • Single Co-IP without rigorous specificity controls; interaction partly inferred from perturbation
    • Functional consequence of TZ-to-axoneme redistribution not established
    • Not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the TMEM231-containing MKS module physically constitutes the diffusion barrier and mechanistically couples barrier integrity to Hedgehog signal transduction remains unresolved.
  • No structural model of the assembled MKS module barrier
  • Direct molecular link between TZ gating and Hedgehog pathway activation undefined
  • Substrate/cargo selectivity of the barrier not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005929 cilium 4 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-162582 Signal Transduction 1
Partners
B9D1CAV1CC2D2AMKS1TMEM107TMEM138
Complex memberships
MKS module (transition zone complex)

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 TMEM231 localizes to the basal body before and independently of intraflagellar transport (IFT), in a Septin 2 (Sept2)-regulated fashion. Its localization at the transition zone is mutually dependent on B9D1 and CC2D2A, and all three require Sept2. Loss of TMEM231 (as part of the complex) reduces cilia formation, causes loss of signaling receptors from remaining cilia, increases the rate of diffusion into the ciliary membrane, and increases plasma-membrane protein in cilia, demonstrating that TMEM231 functions as part of a diffusion barrier complex at the transition zone. RNAi screening, proteomics (complex identification), cell biological assays (ciliogenesis, diffusion rate measurement), mouse knockouts (B9D1 and TMEM231), immunofluorescence localization Nature cell biology High 22179047
2015 TMEM231 is a two-pass transmembrane protein that localizes to the ciliary transition zone and is essential for MKS complex organization. Tmem231 and B9d1 are mutually required for each other's transition zone localization and for Mks1 localization. Loss of Tmem231 in mouse disrupts localization of Arl13b and Inpp5e to cilia, producing polydactyly and kidney cysts. In C. elegans, the TMEM231 orthologue similarly localizes to and controls transition zone formation and function, indicating evolutionary conservation. Mouse knockout (Tmem231 conditional/null), C. elegans genetics, immunofluorescence localization, patient mutation identification with functional validation in cell-based transition zone assays The Journal of cell biology High 25869670
2015 In C. elegans, TMEM-107 organizes the MKS module of transition zone proteins by recruiting TMEM-231 (JBTS20) to an intermediate layer of the transition zone. Super-resolution microscopy revealed periodic localizations of MKS module membrane proteins, including TMEM-231, within the transition zone. MKS module membrane proteins (including TMEM-231) are immobile at the TZ, consistent with a structural scaffold role. C. elegans genetics (tmem-107 mutants), super-resolution fluorescence microscopy (STORM/SIM), FRAP (immobility of MKS module proteins), coexpression/co-evolution bioinformatics to identify candidate TZ genes Nature cell biology High 26595381
2016 In C. elegans, TZ localization of TMEM-231 (orthologue of TMEM231/JBTS20) depends on CEP-290 and is positioned within the CEP-290-dependent MKS assembly pathway. This identifies TMEM231 as an MKS module component whose TZ targeting requires the MKS-5 (Rpgrip1L) and CEP-290-dependent assembly pathway. C. elegans genetics (cep-290 mutants, mks-5 mutants), immunofluorescence/fluorescent protein localization of TMEM-231 at TZ in various mutant backgrounds, epistasis analysis PLoS biology High 26982032
2021 Mouse Tmem231 mutants display hypotelorism due to reduced Hedgehog (HH) pathway activation in the prechordal plate and adjacent neurectoderm, leading to increased cell death in neurectoderm and facial ectoderm. Reducing Ptch1 gene dosage (enhancing HH signaling) rescues the midface defect, placing Tmem231 upstream of HH pathway activation in facial midline development. Mouse genetics (Tmem231 mutants), genetic epistasis (Tmem231; Ptch1 double mutants), immunofluorescence for HH pathway activation markers, cell death assays (TUNEL) eLife High 34672258
2022 TMEM231 interacts reciprocally with TMEM138 and with rhodopsin. In Tmem138 knockout photoreceptors, the ciliary localization of TMEM231 is altered, demonstrating that TMEM138 is required for proper TMEM231 localization at the connecting cilium/transition zone. Co-immunoprecipitation (reciprocal, TMEM138–TMEM231 and TMEM138–rhodopsin), mouse Tmem138 germline knockout, immunofluorescence showing mislocalization of TMEM231 in mutant photoreceptors Proceedings of the National Academy of Sciences of the United States of America Medium 35394880
2023 Caveolin-1 interacts with TMEM231 at the transition zone, and this interaction can be perturbed by exogenous galectin-8. When cilia elongate in response to galectin-8, TMEM231 transitions from the TZ to the growing axoneme, suggesting TMEM231's TZ retention depends partly on its interaction with caveolin-1 within lipid raft domains. Co-immunoprecipitation (caveolin-1 and TMEM231), live/immunofluorescence imaging showing TMEM231 redistribution from TZ to axoneme upon galectin-8 treatment, pharmacological lipid raft disruption FASEB journal Low 37997673
2023 Splice site variants in TMEM231 (c.583-1G>C and c.583-2_588delinsTCCTCCC) cause exon 5 deletion, significantly decrease TMEM231 mRNA expression, and result in near-complete absence of primary cilia in kidney tissue from a Meckel Syndrome fetus, directly linking TMEM231 loss-of-function to primary cilia defects in human kidney. cDNA TA-cloning sequencing (splice effect validation), RT-PCR (expression quantification), immunofluorescence on patient kidney tissue (primary cilia visualization) Frontiers in genetics Medium 37736303

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nature cell biology 288 22179047
2016 MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone. PLoS biology 110 26982032
2015 TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome. Nature cell biology 108 26595381
2017 Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. Journal of medical genetics 87 28289185
2015 TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. The Journal of cell biology 82 25869670
2012 Mutations in TMEM231 cause Joubert syndrome in French Canadians. Journal of medical genetics 62 23012439
2013 Mutations in TMEM231 cause Meckel-Gruber syndrome. Journal of medical genetics 31 23349226
2020 Network study of nasal transcriptome profiles reveals master regulator genes of asthma. The Journal of allergy and clinical immunology 28 32828590
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
2019 Long-read nanopore sequencing resolves a TMEM231 gene conversion event causing Meckel-Gruber syndrome. Human mutation 20 31663672
2020 Genetic tests aid in counseling of fetuses with cerebellar vermis defects. Prenatal diagnosis 19 32386258
2019 High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies. International journal of molecular sciences 17 31323913
2016 TMEM231 Gene Conversion Associated with Joubert and Meckel-Gruber Syndromes in the Same Family. Human mutation 15 27449316
2017 (Pro)renin receptor (ATP6AP2) depletion arrests As4.1 cells in the G0/G1 phase thereby increasing formation of primary cilia. Journal of cellular and molecular medicine 12 28215051
2021 Ciliary Hedgehog signaling regulates cell survival to build the facial midline. eLife 8 34672258
2021 A Novel Homozygous Variant of TMEM231 in a Case With Hypoplasia of the Cerebellar Vermis and Polydactyly. Frontiers in pediatrics 6 34912761
2021 The diagnostic yield of whole exome sequencing as a first approach in consanguineous Omani renal ciliopathy syndrome patients. F1000Research 4 34354814
2025 Whole-exome sequencing screening for candidate genes and potential pathogenic variants associated with early-onset high myopia in 47 Chinese families. Scientific reports 3 40175531
2023 Lipid raft interacting galectin 8 regulates primary ciliogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 3 37997673
2019 Tectocerebellar dysraphia with occipital encephalocele: a phenotypic variant of the TMEM231 gene mutation induced Joubert syndrome. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2 30617574
2023 Identification of novel TMEM231 gene splice variants and pathological findings in a fetus with Meckel Syndrome. Frontiers in genetics 0 37736303

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