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

✍ Scribed by Francesco Brancati; Miriam Iannicelli; Lorena Travaglini; Annalisa Mazzotta; Enrico Bertini; Eugen Boltshauser; Stefano D'Arrigo; Francesco Emma; Elisa Fazzi; Romina Gallizzi; Mattia Gentile; Damir Loncarevic; Vlatka Mejaski-Bosnjak; Chiara Pantaleoni; Luciana Rigoli; Carmelo D. Salpietro; Sabrina Signorini; Gilda Rita Stringini; Alain Verloes; Dominika Zabloka; Bruno Dallapiccola; Joseph G. Gleeson; Enza Maria Valente

• Book ID: 102859587
• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 852 KB
• Volume: 30
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.20924

✦ Synopsis

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.