RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders

Joubert syndrome-related disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the 'molar tooth sign' (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and Meckel-Gruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in 2 of 16 families with cerebello-renal presentation (similar to 12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (< 2%)

AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.

OBJECTIVE: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. METHODS: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. RESULTS: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. INTERPRETATION: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD

MKS3/TMEM67 Mutations Are a Major Cause of COACH Syndrome, a Joubert Syndrome Related Disorder with Liver Involvement.

none25siThe 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.mixedBrancati F; Iannicelli M; Travaglini L; Mazzotta A; Bertini E; Boltshauser E; D'Arrigo S; Emma F; Fazzi E; Gallizzi R; Gentile M; Loncarevic D; Mejaski-Bosnjak V; Pantaleoni C; Rigoli L; Salpietro CD; Signorini S; Stringini GR; Verloes A; Zabloka D; Dallapiccola B; Gleeson JG; Valente EM; International JSRD Study Group; Suppiej ABrancati, F; Iannicelli, M; Travaglini, L; Mazzotta, A; Bertini, E; Boltshauser, E; D'Arrigo, S; Emma, F; Fazzi, E; Gallizzi, R; Gentile, M; Loncarevic, D; Mejaski-Bosnjak, V; Pantaleoni, C; Rigoli, L; Salpietro, Cd; Signorini, S; Stringini, Gr; Verloes, A; Zabloka, D; Dallapiccola, B; Gleeson, Jg; Valente, Em; International JSRD Study, Group; Suppiej,

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