TMEM67 – Joubert syndrome

TMEM67 encodes meckelin, a ciliary transition zone protein essential for primary cilium formation. Autosomal recessive mutations in TMEM67 cause Joubert syndrome type 6, a ciliopathy characterized by cerebellar vermis hypoplasia producing the "molar tooth sign," hypotonia, ataxia, abnormal ocular movements, and variable multiorgan involvement including hepatic fibrosis (COACH syndrome) (PMID:17160906).

Genetic studies in over 50 unrelated probands have identified biallelic TMEM67 variants in Joubert syndrome. In a Japanese cohort, TMEM67 mutations were found in 7/27 families (25.9%) (PMID:27434533); in a prospective series of 100 patients, TMEM67 accounted for 10% of cases with liver and kidney involvement (PMID:28125082). A founder Asn242Ser missense allele was homozygous in 22 affected individuals from 12 Iranian families, segregating with the phenotype in multiple sibships (PMID:28719906). Additional case reports from India, Vietnam, Russia, and the Philippines confirm compound heterozygous missense, splice, and truncating mutations segregating with disease (PMID:26075130; PMID:32000717; PMID:39849212).

The variant spectrum exceeds 70 distinct alleles, including missense (e.g., c.2522A>C (p.Gln841Pro)), frameshift, nonsense, and splice-site changes. Recurrent alleles include p.Asn242Ser in Iranian patients and p.Gln841Pro in multiple ethnicities. Segregation of TMEM67 variants with disease in 19 additional affected relatives underscores pathogenicity (PMID:28719906).

Functional assays demonstrate that meckelin localizes to basal bodies and ciliary membranes, interacting with MKS1 to mediate ciliogenesis. siRNA knockdown of TMEM67 in cultured epithelial cells abolishes cilium formation and epithelial morphogenesis (PMID:17185389). In zebrafish, human wild-type TMEM67 mRNA rescues tmem67 morphant phenotypes, whereas mRNAs harboring patient mutations (e.g., p.Gly132Ala, p.Tyr920ThrfsTer40) fail to rescue, confirming loss-of-function (PMID:28860541).

No credible conflicting evidence has been reported; mild isolated cholestasis cases expand the phenotypic spectrum but do not dispute the association with Joubert syndrome (PMID:35621037).

Overall, AR TMEM67 variants consistently cause Joubert syndrome through impaired ciliogenesis, with robust genetic and functional concordance. TMEM67 mutation analysis is clinically actionable for diagnosis, prognosis, genetic counseling, and guiding surveillance of neurologic, renal, and hepatic complications. Key take-home: TMEM67 testing is essential for precise diagnosis and management of Joubert syndrome.

References

• American journal of human genetics • 2007 • The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. PMID:17160906
• Clinical genetics • 2016 • Molecular genetic analysis of 30 families with Joubert syndrome. PMID:27434533
• Genetics in medicine • 2017 • Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center. PMID:28125082
• Public health genomics • 2017 • A Common Ancestral Asn242Ser Mutation in TMEM67 Identified in Multiple Iranian Families with Joubert Syndrome. PMID:28719906
• Case reports in pediatrics • 2015 • Molar Tooth Sign with Deranged Liver Function Tests: An Indian Case with COACH Syndrome. PMID:26075130
• 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

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