Affinage

TMEM216

Transmembrane protein 216 · UniProt Q9P0N5

Length
145 aa
Mass
16.5 kDa
Annotated
2026-06-10
43 papers in source corpus 9 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM216 is a tetraspan transmembrane protein of the ciliary transition zone that governs ciliogenesis, ciliary membrane composition, and ciliary stability (PMID:20512146, PMID:21725307). It assembles into the MKS/Joubert syndrome transition-zone complex together with Meckelin/TMEM67, Mks1, Cep290, B9d1, Tctn1/Tctn2, and Cc2d2a, where these components co-localize at the ciliary base and collectively maintain the membrane gate that controls entry of ciliary membrane proteins such as Arl13b, Smoothened, and Pkd2 (PMID:20512146, PMID:21725307). Loss of TMEM216 disrupts centrosomal docking and ciliogenesis with downstream hyperactivation of RhoA and Dishevelled (PMID:20512146), and at the distal transition zone TMEM216 restrains constitutive ciliary shedding (PMID:32163404). Beyond its structural role, TMEM216 acts in Hedgehog signaling by binding GLI2/GLI3 and competing with the repressor SUFU, thereby blocking GLI cleavage to promote nuclear accumulation of full-length GLI2 and pathway activation (PMID:38261656). Its function is genetically and transcriptionally coordinated with TMEM138 through a shared cis-regulatory module that supports interdependent vesicular transport to cilia (PMID:22282472). In vivo, loss causes photoreceptor outer-segment protein mislocalization and degeneration (PMID:32687549) and ciliopathic phenotypes consistent with its identification as a Joubert/Meckel syndrome gene (PMID:20512146).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 High

    Established TMEM216 as a transition-zone protein whose loss disrupts ciliogenesis, answering whether it has a direct ciliary function and linking it to ciliopathy.

    Evidence Immunofluorescence localization plus siRNA knockdown and RhoA/Dishevelled activity assays in fibroblasts

    PMID:20512146

    Open questions at the time
    • Molecular basis of RhoA/Dishevelled hyperactivation not resolved
    • Direct binding partners at the transition zone not defined in this study
  2. 2010 Medium

    First physical partner identified, placing TMEM216 in the same molecular machinery as another Joubert/Meckel gene product.

    Evidence Co-immunoprecipitation of TMEM216 with Meckelin/TMEM67

    PMID:20512146

    Open questions at the time
    • Single Co-IP, not reciprocally validated in the corpus
    • Stoichiometry and direct vs. indirect interaction unclear
  3. 2010 Medium

    Provided in vivo evidence of ciliary dysfunction from TMEM216 loss in a vertebrate model.

    Evidence Morpholino knockdown in zebrafish with gastrulation/ciliary phenotype analysis

    PMID:20512146

    Open questions at the time
    • Morpholino off-target effects not excluded
    • Tissue-specific requirements not addressed
  4. 2011 High

    Defined TMEM216 as a member of a multi-protein transition-zone complex that controls ciliary membrane composition, establishing the gate function.

    Evidence Reciprocal co-IP complex assembly, co-localization, and loss-of-function with ciliary membrane readouts (Arl13b, AC3, Smoothened, Pkd2) across complex members

    PMID:21725307

    Open questions at the time
    • Spatial architecture of TMEM216 within the complex not resolved
    • Mechanism of selective membrane protein exclusion not defined
  5. 2011 Medium

    Showed functional cooperation between TMEM216 and TMEM237 in anchoring the basal body/transition zone to the membrane.

    Evidence C. elegans double-mutant genetic interaction and ciliogenesis assays

    PMID:22152675

    Open questions at the time
    • Genetic interaction does not establish direct physical contact
    • Single model organism
  6. 2012 High

    Revealed a shared cis-regulatory mechanism coordinating TMEM216 with TMEM138 and linked both to vesicular transport to cilia.

    Evidence Comparative genomics, reporter assays for the shared intergenic element, and vesicular transport assays

    PMID:22282472

    Open questions at the time
    • Molecular cargo of the vesicular transport pathway not identified
    • Whether TMEM216 and TMEM138 physically interact not established
  7. 2016 Medium

    Identified TMEM216 as a genetic modifier of nphp-4-related ciliary phenotypes, broadening its functional network.

    Evidence C. elegans forward modifier screen with dye-filling and osmotic avoidance assays

    PMID:26863025

    Open questions at the time
    • Mechanism of interaction with NPHP module unresolved
    • Genetic, not physical, interaction
  8. 2020 High

    Demonstrated that TMEM216 restrains ciliary shedding and pinpointed its distal transition-zone localization with 9-fold symmetry.

    Evidence RNAi in Paramecium, live cilia imaging, and symmetry-resolved immunofluorescence

    PMID:32163404

    Open questions at the time
    • Molecular trigger of deciliation upon loss not defined
    • Conservation of shedding role in mammalian cilia not tested here
  9. 2020 High

    Established a tissue-specific requirement in photoreceptors, connecting TMEM216 loss to outer-segment protein trafficking and degeneration.

    Evidence CRISPR knockout zebrafish with immunofluorescence, electron microscopy, and TUNEL

    PMID:32687549

    Open questions at the time
    • Mechanism of outer-segment protein mislocalization not resolved
    • Whether degeneration is cell-autonomous not addressed
  10. 2021 Medium

    Defined a close functional association between TMEM216 and the B9 complex at the transition zone using patient-variant knock-ins.

    Evidence C. elegans CRISPR knock-in of B9D2 JBTS variants with quantitative TZ structure assays and compound-heterozygous recapitulation

    PMID:33234550

    Open questions at the time
    • Direct biochemical interaction with B9 complex not shown
    • Findings in invertebrate model
  11. 2024 High

    Extended TMEM216 beyond a structural transition-zone role to a direct regulator of Hedgehog signaling through SUFU/GLI competition.

    Evidence Reciprocal Co-IP (SUFU, GLI2/GLI3), competition binding, nuclear fractionation, and Tmem216 knockout mouse Hh readouts

    PMID:38261656

    Open questions at the time
    • How a transition-zone transmembrane protein accesses cytoplasmic GLI/SUFU not mechanistically explained
    • Structural basis of GLI binding not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMEM216's transition-zone gating function is mechanistically coupled to its Hedgehog-regulatory role, and the structural basis of its protein interactions, remain unresolved.
  • No structural model of TMEM216 or its complexes
  • Mechanism linking membrane gate integrity to GLI regulation unknown
  • Direct cargo of TMEM216/TMEM138 vesicular transport unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005929 cilium 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-162582 Signal Transduction 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
B9D1CC2D2ACEP290MKS1SUFUTCTN1TCTN2TMEM67
Complex memberships
MKS/Joubert transition-zone complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 TMEM216 encodes a tetraspan transmembrane protein that localizes to the base of primary cilia (transition zone). Loss of TMEM216 in mutant fibroblasts or after siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. Immunofluorescence localization, siRNA knockdown in fibroblasts, functional ciliogenesis assay, RhoA/Dishevelled activity assays Nature genetics High 20512146
2010 TMEM216 forms a protein complex with Meckelin (MKS3/TMEM67), a protein encoded by another gene mutated in Joubert and Meckel syndromes. Co-immunoprecipitation Nature genetics Medium 20512146
2010 Disruption of tmem216 expression in zebrafish caused gastrulation defects consistent with ciliary dysfunction (similar to other ciliary morphants). Morpholino knockdown in zebrafish, phenotypic analysis Nature genetics Medium 20512146
2011 TMEM216 is a component of a transition zone complex including Mks1, Tmem67, Cep290, B9d1, Tctn2, Cc2d2a, and Tctn1. Components of this complex co-localize at the transition zone. Loss of complex components causes tissue-specific defects in ciliogenesis and ciliary membrane composition (mislocalization of Arl13b, AC3, Smoothened, Pkd2). Co-immunoprecipitation complex assembly, immunofluorescence co-localization, genetic loss-of-function with ciliary membrane composition readouts Nature genetics High 21725307
2012 TMEM216 and TMEM138 are arranged head-to-tail on chromosome 11 and share a conserved cis-regulatory element in the intergenic region that mediates coordinated expression. Their coordinated expression is important for an interdependent cellular role in vesicular transport to primary cilia. Comparative genomics, reporter gene assays for shared regulatory element, cellular vesicular transport assays Science (New York, N.Y.) High 22282472
2011 In C. elegans, MKS-2/TMEM216 functionally interacts with JBTS-14/TMEM237 to control basal body-transition zone anchoring to the membrane and ciliogenesis, as demonstrated by genetic interaction assays. C. elegans genetic interaction (double mutant analysis), ciliogenesis assay American journal of human genetics Medium 22152675
2020 In Paramecium, depletion of MKS2/TMEM216 induces constitutive deciliation of some cilia, revealing a role for TMEM216 at the transition zone in controlling ciliary shedding. TMEM216 localizes with 9-fold symmetry at the most distal part of the transition zone in growing cilia. RNAi knockdown in Paramecium, live imaging of cilia, immunofluorescence localization with 9-fold symmetry analysis PLoS biology High 32163404
2020 TMEM216 deletion in zebrafish (CRISPR knockout) leads to shortened photoreceptor ciliary axoneme, mislocalization of outer segment proteins (rhodopsin, GNAT2, red opsin) to inner segments and cell bodies, abnormal outer segment disc morphology, and photoreceptor degeneration. CRISPR/Cas9 knockout zebrafish, immunofluorescence, electron microscopy, TUNEL assay Investigative ophthalmology & visual science High 32687549
2021 In C. elegans, a very close functional association exists between the B9D2-associated B9 complex and MKS-2/TMEM216 at the transition zone, as revealed by compound heterozygous allele knock-in experiments showing that B9D2 JBTS variants disrupt endogenous MKSR-2 organisation at the TZ and worsen MKS-2-related phenotypes. C. elegans CRISPR knock-in of patient variants, quantitative TZ/cilium structure assays, compound heterozygous genotype recapitulation Disease models & mechanisms Medium 33234550
2024 TMEM216 interacts directly with SUFU (a negative regulator of Hedgehog signaling) and with GLI2/GLI3 transcription factors. TMEM216 competes with SUFU for binding to GLI2/GLI3, inhibiting their cleavage into repressor forms, resulting in nuclear accumulation of full-length GLI2 and decreased nuclear localization of cleaved GLI3, thereby activating Hedgehog signaling. Tmem216-deficient mice display impaired Hh signaling and ciliopathic phenotypes. Co-immunoprecipitation (TMEM216-SUFU, TMEM216-GLI2/GLI3), competition binding assay, nuclear fractionation, Tmem216 knockout mouse with Hh target gene expression readouts, cell-based Hh signaling assays Science signaling High 38261656
2016 In C. elegans, mks-2 (TMEM216 ortholog) genetically interacts with nphp-4 to modulate ciliary defects, identified in a modifier screen; mks-2 mutations exacerbate nphp-4 ciliary phenotypes. C. elegans forward genetic modifier screen, double-mutant analysis, cilia phenotype assays (dye-filling, osmotic avoidance) PLoS genetics Medium 26863025

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nature genetics 524 21725307
2010 Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nature genetics 227 20512146
2006 The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nature genetics 219 16415887
2007 Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. American journal of human genetics 215 17564974
2011 TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. American journal of human genetics 165 22152675
1984 Superkiller mutations in Saccharomyces cerevisiae suppress exclusion of M2 double-stranded RNA by L-A-HN and confer cold sensitivity in the presence of M and L-A-HN. Molecular and cellular biology 122 6371496
2010 Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy. Journal of medical genetics 113 21068128
2011 Engineering of bacterial methyl ketone synthesis for biofuels. Applied and environmental microbiology 91 22038610
2008 C2cd3 is required for cilia formation and Hedgehog signaling in mouse. Development (Cambridge, England) 85 19004860
2009 Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. American journal of human genetics 82 20036350
2003 Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. American journal of human genetics 74 12917796
2007 Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online. Human mutation 72 17397051
2012 Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. Science (New York, N.Y.) 71 22282472
2003 Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation. American journal of human genetics 68 12908130
2011 B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. Human molecular genetics 67 21493627
2005 Distinguishing the four genetic causes of Jouberts syndrome-related disorders. Annals of neurology 66 15786477
2013 C5orf42 is the major gene responsible for OFD syndrome type VI. Human genetics 63 24178751
1998 A gene for Meckel syndrome maps to chromosome 11q13. American journal of human genetics 62 9758620
2013 Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome. American journal of human genetics 46 23972372
2009 Multiple biochemical and morphological factors underlie the production of methylketones in tomato trichomes. Plant physiology 46 19801397
2012 Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies. Cilia 43 23351400
2010 Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Molecular neurobiology 42 21110233
2007 Meckel syndrome: genetics, perinatal findings, and differential diagnosis. Taiwanese journal of obstetrics & gynecology 42 17389183
2002 A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24. Human genetics 33 12384791
2020 MKS-NPHP module proteins control ciliary shedding at the transition zone. PLoS biology 31 32163404
2021 Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans. Disease models & mechanisms 27 33234550
2022 Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. Disease models & mechanisms 17 36533556
2016 A Screen for Modifiers of Cilia Phenotypes Reveals Novel MKS Alleles and Uncovers a Specific Genetic Interaction between osm-3 and nphp-4. PLoS genetics 17 26863025
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
2020 TMEM216 Deletion Causes Mislocalization of Cone Opsin and Rhodopsin and Photoreceptor Degeneration in Zebrafish. Investigative ophthalmology & visual science 9 32687549
2023 Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome. Journal of medical genetics 8 36788019
2024 TMEM216 promotes primary ciliogenesis and Hedgehog signaling through the SUFU-GLI2/GLI3 axis. Science signaling 7 38261656
2024 Substitution of a single non-coding nucleotide upstream of TMEM216 causes non-syndromic retinitis pigmentosa and is associated with reduced TMEM216 expression. American journal of human genetics 7 39191256
2018 Determination of candidate genes involved in schizophrenia using the whole-exome sequencing. Bratislavske lekarske listy 7 30226068
2019 Characterization of Solanum melongena Thioesterases Related to Tomato Methylketone Synthase 2. Genes 6 31323901
2004 Comparative physical maps of the human and mouse Meckel syndrome critical regions. Mammalian genome : official journal of the International Mammalian Genome Society 6 15112103
2024 Exploration of lncRNA/circRNA-miRNA-mRNA network in patients with chronic atrophic gastritis in Tibetan plateau areas based on DNBSEQ-G99 RNA sequencing. Scientific reports 5 38649401
2012 Basal vertebrates clarify the evolutionary history of ciliopathy-associated genes Tmem138 and Tmem216. Molecular biology and evolution 4 22936720
2019 Identification and Functional Characterization of a Soybean (Glycine max) Thioesterase that Acts on Intermediates of Fatty Acid Biosynthesis. Plants (Basel, Switzerland) 3 31597241
2018 Thumb duplication: molecular analysis of different clinical types. European journal of orthopaedic surgery & traumatology : orthopedie traumatologie 3 30498907
2025 Identification of a Sinorhizobium meliloti YbgC-like thioesterase that contributes to the production of the infochemical 2-tridecanone. The Biochemical journal 1 40938124
2024 Novel PIBF1 Pathogenic Variant in Three Siblings with Joubert Syndrome Type 33. Molecular syndromology 1 41230208
2025 Renal insufficiency caused by TMEM216 gene mutation: Case Report. Frontiers in medicine 0 40365501

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