MKS3/TMEM67mutations 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.

The role of primary cilia in the development and disease of the retina

“…66 Mutations in human TMEM67 are associated with a suite of ciliopathies, many of which include retinal degeneration phenotypes. [67][68][69] Many retinal proteins also need to be correctly localized to the CC membrane. The cilium membrane is the site of many G-protein coupled receptors (GPCRs), mediating many important roles in cellular signaling.…”

Retinal Abnormalities Characteristic of Inherited Renal Disease

“…42 MSK3 mutations account for nearly 60% of cases. 43 Patients may have the molar tooth sign, a midbrain-hindbrain malformation also seen in Joubert syndrome and congenital hepatic fibrosis. Although they have medullary renal cysts, they do not necessarily develop renal failure.…”

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

“…2 It is estimated that known genes overall account for about half of cases, suggesting further genetic heterogeneity; moreover, genotype-phenotype correlates have been clearly established only for few JSRD-causative genes. [5][6][7][8][9] In 2009, Jacoby et al 10 identified INPP5E mutations in a family with MORM syndrome, a rare autosomal recessive condition related to Bardet-Biedl syndrome. In the same year, we identified homozygous INPP5E mutations in seven consanguineous families genetically linked to the first JSRD locus (JBTS1) on 9q34.…”