MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.
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.
Brancati
Francesco
F
IRCCS CSS-Mendel Institute, Rome, Italy.
Iannicelli
Miriam
M
Travaglini
Lorena
L
Mazzotta
Annalisa
A
Bertini
Enrico
E
Boltshauser
Eugen
E
D'Arrigo
Stefano
S
Emma
Francesco
F
Fazzi
Elisa
E
Gallizzi
Romina
R
Gentile
Mattia
M
Loncarevic
Damir
D
Mejaski-Bosnjak
Vlatka
V
Pantaleoni
Chiara
C
Rigoli
Luciana
L
Salpietro
Carmelo D
CD
Signorini
Sabrina
S
Stringini
Gilda Rita
GR
Verloes
Alain
A
Zabloka
Dominika
D
Dallapiccola
Bruno
B
Gleeson
Joseph G
JG
Valente
Enza Maria
EM
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
D008565:Membrane Proteins; D022821:RNA Splice Sites; C468846:TMEM67 protein, human