TMEM216 – Meckel Syndrome

Meckel syndrome (MKS) is a rare autosomal recessive lethal ciliopathy characterized by occipital meningo-encephalocele, multicystic renal dysplasia, hepatic fibrosis and postaxial polydactyly (HP:0100259). Early mapping efforts identified genetic heterogeneity for MKS, with one locus (MKS1) on 17q21–q24 and a second locus (MKS2) on 11q13.

Homozygosity mapping in seven consanguineous Middle Eastern and North African MKS families yielded a maximum LOD score of 4.41 at chromosome 11q13, and affected fetuses of southern Tunisian ancestry shared a founder haplotype at D11S911 and D11S906, demonstrating linkage of TMEM216 to MKS2 in 7 families ([PMID:9758620]).

Subsequent allelism studies showed that TMEM216 mutations cause both Joubert syndrome and MKS2. A recurrent G218T (p.Arg73Leu) founder mutation was identified in 10 Ashkenazi Jewish probands, and fetuses with MKS exhibited skeletal dysplasia consistent with AR inheritance ([PMID:20512146]).

The TMEM216 variant spectrum in MKS includes loss-of-function alleles and splice-site changes. A representative truncating allele is c.250C>T (p.Gln84Ter) which is predicted to abolish TMEM216 function through premature termination of translation ([PMID:20512146]).

Founder segregation is supported by a shared haplotype in 7 Tunisian families and a recurrent p.Arg73Leu variant in 10 independent Ashkenazi Jewish probands, confirming autosomal recessive transmission and multi-family segregation of TMEM216 alleles ([PMID:9758620]; [PMID:20512146]).

Functional assays localize TMEM216 to the base of primary cilia, and TMEM216 knockdown in patient fibroblasts causes defective ciliogenesis, centrosomal docking defects with RhoA and Dishevelled hyperactivation. Zebrafish tmem216 morphants recapitulate gastrulation and ciliary phenotypes, supporting a loss-of-function mechanism ([PMID:20512146]).

Additional studies of ciliary transition zone mutants in zebrafish demonstrate variable tissue-specific functions and phenotypic penetrance for tmem216, consistent with modifier influences and spectrum of ciliopathy presentations ([PMID:36533556]).

In summary, TMEM216 is robustly associated with autosomal recessive Meckel syndrome by multi-family linkage, recurrent founder variants, and concordant functional evidence. Key take-home: TMEM216 mutation analysis informs molecular diagnosis, genetic counseling and prenatal testing for MKS.

References

• American journal of human genetics • 1998 • A gene for Meckel syndrome maps to chromosome 11q13. PMID:9758620
• Nature genetics • 2010 • Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. PMID:20512146
• Disease models & mechanisms • 2022 • Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. PMID:36533556

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