TMEM67 – Joubert syndrome 6

TMEM67 encodes meckelin, a transition zone protein essential for primary cilium structure and signaling. Biallelic variants in TMEM67 cause Joubert syndrome 6, an autosomal recessive ciliopathy characterized by cerebellar vermis hypoplasia and the classical “molar tooth sign” (TMEM67, Joubert syndrome 6).

JS6 follows an autosomal recessive inheritance pattern. To date, 12 unrelated probands have been reported with biallelic TMEM67 variants, including a homozygous Asn242Ser in a child with JS6 (PMID:39027323), three children from multiplex families with compound heterozygous or homozygous variants (PMID:19540516), and eight Joubert patients with liver involvement identified among 265 JSRD cases (PMID:20232449).

Segregation of TMEM67 variants has been demonstrated in consanguineous and multiplex pedigrees, with alleles co-segregating with the JS6 phenotype across three independent families (PMID:19540516). No studies have reported conflicting clinical or genetic evidence.

The TMEM67 variant spectrum in JS6 includes eight missense changes (e.g., c.725A>G (p.Asn242Ser) PMID:39027323, c.395G>C (p.Gly132Ala) PMID:28860541), five frameshift/nonsense variants (e.g., c.2758del (p.Tyr920ThrfsTer) PMID:28860541, c.157C>T (p.Gln53Ter) PMID:20232449), and canonical splice-site defects (c.869+1G>C) PMID:20232449, consistent with a loss-of-function mechanism.

Functional assays corroborate pathogenicity and mechanism: meckelin localizes to basal bodies and interacts with MKS1 to mediate cilium formation (PMID:17185389); zebrafish tmem67 morphant phenotypes are rescued by wild-type but not mutant TMEM67 (PMID:28860541); and C. elegans knock-in of human variants disrupts transition zone structure and ciliary function (PMID:34964473).

In summary, autosomal recessive TMEM67 variants cause JS6 through impaired meckelin function and defective ciliogenesis. Molecular testing for TMEM67 in patients with the molar tooth sign and compatible systemic features offers definitive diagnosis and informs genetic counseling.

References

• American Journal of Ophthalmology Case Reports • 2024 • Novel ocular observations in a child with Joubert syndrome type 6 due to pathogenic variant in TMEM67 gene. PMID:39027323
• Human mutation • 2010 • Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. PMID:20232449
• The Journal of pediatrics • 2009 • MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome. PMID:19540516
• Human molecular genetics • 2007 • The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. PMID:17185389
• Scientific reports • 2017 • Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome. PMID:28860541
• Human molecular genetics • 2022 • Interpreting ciliopathy-associated missense variants of uncertain significance (VUS) in Caenorhabditis elegans. PMID:34964473

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