MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.


Journal Article

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.

Full Text

Duke Authors

Cited Authors

  • Brancati, F; Iannicelli, M; Travaglini, L; Mazzotta, A; Bertini, E; Boltshauser, E; D'Arrigo, S; Emma, F; Fazzi, E; Gallizzi, R; Gentile, M; Loncarevic, D; Mejaski-Bosnjak, V; Pantaleoni, C; Rigoli, L; Salpietro, CD; Signorini, S; Stringini, GR; Verloes, A; Zabloka, D; Dallapiccola, B; Gleeson, JG; Valente, EM; International JSRD Study Group,

Published Date

  • February 2009

Published In

Volume / Issue

  • 30 / 2

Start / End Page

  • E432 - E442

PubMed ID

  • 19058225

Pubmed Central ID

  • 19058225

Electronic International Standard Serial Number (EISSN)

  • 1098-1004

International Standard Serial Number (ISSN)

  • 1059-7794

Digital Object Identifier (DOI)

  • 10.1002/humu.20924


  • eng