TMEM67 – Meckel syndrome

Meckel syndrome (MKS) is a perinatally lethal, autosomal recessive hepatorenal fibrocystic disorder characterized by occipital encephalocoele, multicystic kidney dysplasia, hepatic fibrosis, and postaxial polydactyly. Initial human genetic studies in 120 independent MKS cases identified TMEM67 (MKS3) variants in 8/120 (7%) unrelated probands, including a recurrent splice-site mutation c.1575+1G>A segregating in five sibships from three families (PMID:17397051). In a separate cohort of 76 MKS fetuses, TMEM67 mutations were found in 12/76 (16%) cases (PMID:20232449), and six additional unrelated fetal cases carried novel TMEM67 alleles (PMID:31411728). A recent case report of recurrent pregnancy loss described biallelic TMEM67 variants (c.2314del (p.Met772Ter) and c.1415T>G (p.Val472Gly)) in a family consistent with lethal MKS3 (PMID:38844949). Segregation analysis across multiple consanguineous and sibship-based families demonstrated co-segregation of TMEM67 variants with disease in at least 8 additional affected relatives.

All reported TMEM67 variants are consistent with autosomal recessive inheritance. The variant spectrum includes at least 4 recurrent founder alleles (e.g., c.1575+1G>A) and a broad range of loss-of-function changes (nonsense, frameshift, splice-site) plus pathogenic missense substitutions clustering in exons encoding the extracellular domain. The most frequently observed missense mutation is c.1318C>T (p.Arg440Trp), identified in Pakistani and European MKS pedigrees (PMID:17397051; PMID:20232449).

Functional studies across species confirm a loss-of-function mechanism. In zebrafish, human TMEM67 mRNA harboring p.Arg440Trp fails to rescue mks-3 morphants (PMID:28487520). In a large animal (ovine) model, homozygous p.Ile681Asn and p.Ile687Ser mutations cause dysmorphic primary cilia, renal cysts, and hepatic fibrosis; zebrafish rescue assays validated their pathogenicity (PMID:28487520). siRNA-mediated knockdown of meckelin in cultured epithelial cells blocked ciliogenesis, and co-immunoprecipitation showed loss of MKS1–meckelin interaction (PMID:17185389). A spontaneous Tmem67 deletion in mice recapitulates polycystic kidney disease, hydrocephalus, and perinatal lethality, rescued by transgenic TMEM67 (PMID:19211713).

Animal and cellular models consistently demonstrate that TMEM67 deficiency disrupts primary cilium formation and length control, leading to fibrocystic changes in kidney and liver. These data are concordant with human phenotypes and support haploinsufficiency or complete loss of function as the primary pathogenic mechanism.

No credible conflicting evidence has been reported; TMEM67 has been robustly and repeatedly implicated in MKS across >15 years of genetic and functional studies. Additional evidence, including deeper population screening and quantitative phenotype modifiers, exists but exceeds current scoring limits.

Key Take-home: TMEM67 loss-of-function variants are definitively associated with autosomal recessive Meckel syndrome, and genetic testing for TMEM67 should be included in diagnostic panels for prenatal or neonatal presentations of fibrocystic kidney and liver disease.

References

• Scientific reports • 2017 • An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations PMID:28487520
• Human mutation • 2007 • Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation PMID:17397051
• Human mutation • 2010 • Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies PMID:20232449
• Clinical genetics • 2019 • Meckel syndrome: Clinical and mutation profile in six fetuses PMID:31411728
• BMC medical genomics • 2024 • Two novel TMEM67 variations in a Chinese family with recurrent pregnancy loss: a case report PMID:38844949
• Human molecular genetics • 2007 • The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation PMID:17185389
• Journal of the American Society of Nephrology • 2009 • A mouse model for Meckel syndrome type 3 PMID:19211713

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