The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat

Abstract

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.

Missense variants in TMEM67 in a patient with Joubert syndrome

“…This results in a change from the amino acid cysteine at position 173 to an arginine: c.517T>C; p.(Cys173Arg). This amino acid change falls in a cysteine‐rich domain in TMEM67 that spans amino acids 50‐18712 and mediates signaling through WNT5A interactions 8, 14. Mutations in similar regions in TMEM67 have been found in patients with Joubert syndrome and Joubert syndrome with the COACH (cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis) phenotype.…”

Primary cilia signaling mediates intraocular pressure sensation

“…The Wistar polycystic kidney (Wpk) rat is a well-established model for studying ciliopathy, as these animals develop hydrocephalus (41). Previous work showed Wpk rats responded to TRPV4-targeted treatment in hydrocephalus; we thus used these animals to test the effect of TRPV4 agonist treatment on eye pressure.…”

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

“…4 Subsequently, nine additional genes have been identified, all similarly encoding ciliary proteins (TMEM216 (MKS2), TMEM67 (MKS3), CEP290 (MKS4), RPGRIP1L (MKS5), CC2D2A (MKS6), NPHP3 (MKS7), TCTN2 (MKS8), B9D1 (MKS9) and B9D2 (MKS10)). [4][5][6][7][8][9][10][11][12][13][14] The finding that defective ciliary biology is the core molecular pathology of MKS made it possible to dissect the pathogenesis of each of its manifestations. For instance, the primary cilium plays a critical role in SHH signaling that controls anteriorposterior and dorsal-ventral patterning of the developing limb buds and neural tube, respectively, thus explaining the polydactyly and neural tube defects that characterize MKS at the molecular level.…”