title: MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.
abstract: 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.
authors.affiliation: IRCCS CSS-Mendel Institute, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Miriam
authors.initials: M
authors.lastname: Iannicelli
authors.forename: Lorena
authors.initials: L
authors.lastname: Travaglini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Mazzotta
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.forename: Stefano
authors.initials: S
authors.lastname: D'Arrigo
authors.forename: Francesco
authors.initials: F
authors.lastname: Emma
authors.forename: Elisa
authors.initials: E
authors.lastname: Fazzi
authors.forename: Romina
authors.initials: R
authors.lastname: Gallizzi
authors.forename: Mattia
authors.initials: M
authors.lastname: Gentile
authors.forename: Damir
authors.initials: D
authors.lastname: Loncarevic
authors.forename: Vlatka
authors.initials: V
authors.lastname: Mejaski-Bosnjak
authors.forename: Chiara
authors.initials: C
authors.lastname: Pantaleoni
authors.forename: Luciana
authors.initials: L
authors.lastname: Rigoli
authors.forename: Carmelo D
authors.initials: CD
authors.lastname: Salpietro
authors.forename: Sabrina
authors.initials: S
authors.lastname: Signorini
authors.forename: Gilda Rita
authors.initials: GR
authors.lastname: Stringini
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Dominika
authors.initials: D
authors.lastname: Zabloka
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D006801:Humans; D008099:Liver / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D013577:Syndrome
chemical_list: D008565:Membrane Proteins; D022821:RNA Splice Sites; C468846:TMEM67 protein, human