TMEM67 – Ciliopathy

TMEM67 encodes meckelin, a transmembrane receptor localized to the primary cilium and basal body. Biallelic loss-of-function or hypomorphic variants in TMEM67 cause autosomal recessive ciliopathies, spanning Meckel syndrome, Joubert spectrum disorders, COACH syndrome and isolated nephronophthisis. The broad phenotypic umbrella is captured under MONDO:0005308 (ciliopathy; TMEM67).

Genetic evidence supports an autosomal recessive inheritance mode, with at least 20 unrelated probands harboring biallelic TMEM67 variants across multiple studies. A consanguineous MKS-like patient with an in-frame C-terminal deletion established segregation of an allele abrogating meckelin–filamin A interaction (c.2754_2756del (p.Phe919del)) (PMID:22121117). Prenatal sequencing of eight ciliopathy fetuses from five families identified compound heterozygous missense and nonsense variants in TMEM67 in three families (PMID:34675960). A cohort of 341 probands (265 Joubert spectrum, 76 Meckel fetuses) yielded 33 distinct TMEM67 mutations in 20 individuals, confirming a strong gene-disease link (PMID:20232449).

The TMEM67 variant spectrum includes missense, nonsense, frameshift, splice-site and small in-frame deletions, with clustering of pathogenic alleles in exons 8–15 of the extracellular domain. Functional silent variants (e.g., c.2439G>A (p.Ala813=)) have also been reported, though their impact remains under investigation. No clear founder alleles have been identified.

Experimental studies demonstrate that meckelin directly binds filamin A at the basal body; the Phe919 deletion disrupts this interaction, impairs basal body positioning and blocks ciliogenesis in patient cells and Flna-null mouse embryos (PMID:22121117). Zebrafish morpholino knockdown of flna exacerbates mks3 phenotypes, and siRNA depletion of filamin A phenocopies meckelin loss. In C. elegans, CRISPR knock-ins of human TMEM67 VUS distinguish pathogenic from benign variants via ciliary dye-filling and chemotaxis assays, corroborated by human cell rescue studies (PMID:34964473).

Together, genetic segregation and diverse functional assays support a loss-of-function mechanism for TMEM67 in autosomal recessive ciliopathies. While most variants cause severe multisystem disease, hypomorphic alleles may underlie milder phenotypes such as isolated cholestasis or nephronophthisis.

Key Take-home: TMEM67 harbors pathogenic recessive alleles that disrupt ciliogenesis and basal body positioning, and should be included in diagnostic panels for AR ciliopathies.

References

• Human molecular genetics • 2012 • A meckelin-filamin A interaction mediates ciliogenesis. PMID:22121117
• Human mutation • 2010 • Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. PMID:20232449
• Frontiers in genetics • 2021 • Molecular Diagnosis and Prenatal Phenotype Analysis of Eight Fetuses With Ciliopathies. PMID:34675960
• Human molecular genetics • 2022 • Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) in Caenorhabditis elegans. PMID:34964473

Evidence Based Scoring (AI generated)