Expanding CEP290 mutational spectrum in ciliopathies

Abstract

Ciliopathies are an expanding group of rare conditions characterised by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus, that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Identification of Mutations Causing Inherited Retinal Degenerations in the Israeli and Palestinian Populations Using Homozygosity Mapping

“…51 The CEP290 mutations affect photoreceptor development or maturation and cause EORP or LCA. [52][53][54] Family MOL0226 is a consanguineous Arab-Christian family with two children affected with LCA (Fig. 3).…”

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

“…In patient COR28, in whom only a single heterozygous mutation could be detected, genomic quantitative real-time PCR (qPCR) of all exons was performed to search for deletions or duplications, as described. 13 Primers and PCR conditions are available upon request.…”

Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish

“…Other physical deformities may include polydactyly, cleft palate, renal cysts, and liver disease. A rapidly expanding number of genes have been implicated in Joubert syndrome, including NPHP1, NPHP6/CEP290, NPHP8, ARL13B and INPP5E (Arts, et al, 2007, Bielas et al, 2009, Cantagrel, et al, 2008, Kim, et al, 2008, McEwen, et al, 2007, Travaglini, et al, 2009, Valente, et al, 2010). …”