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. 2009 Feb;30(2):E432-42.
doi: 10.1002/humu.20924.

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

Francesco Brancati  1 , 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; International JSRD Study Group
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MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement

Francesco Brancati et al. Hum Mutat. 2009 Feb.

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.

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Figures

Figure 1
Figure 1
A) Schematic of the MKS3 gene (cDNA reference sequence: NM_153704.4) and B) of the meckelin protein (reference sequence: NP_714915.3) with mutations identified in the present study (*, possibly damaging; ** probably damaging). Splice site mutations are not represented at the protein level. TM, predicted transmembrane domains (Khaddour et al., 2007). C) Conservation across species (shaded in yellow) of residues affected by novel missense variants.
Figure 2
Figure 2
Characterization of the splicing mutation c.G1961-2A>C in family COR09. A) Agarose gel electrophoresis of the 477bp cDNA fragment showing the generation of an abnormal band of approximately 230bp in the proband. B) Electropherograms of the two fragments from the proband: mRNAwt shows the expected exon 18–19 junction, while mRNA1 presents an abnormal exon18–21 junction, with skipping of exons 19 and 20. M: 100bp marker; C: control; P: proband; NT: no transcript.
Figure 3
Figure 3
Axial (upper lane) and median sagittal (lower lane) brain MRI sections of six probands showing the typical “molar tooth sign” and associated CNS malformations (see text).
See this image and copyright information in PMC

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