Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype

Abstract

Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration responsible for congenital blindness. Hitherto, 13 LCA genes have been mapped, nine of which have been identified. Recently, mutations in the NPHP6/CEP290 gene were shown to account for Joubert and Senior-Loken syndromes and to represent a frequent cause of isolated LCA. All LCA patients shared an intronic mutation resulting in an aberrantly spliced transcript and low levels of wild-type transcript that was believed to explain the absence of cerebellar and renal involvement in these patients. Here, we confirm the high frequency of NPHP6/CEP290 mutations in our series of LCA families hailing worldwide (22%). However, we show that conversely to other LCA genes, NPHP6 is involved in families of European descent only (38/38). A total of 24 different mutations were found, 23 of which are novel (one founder mutation in the North region of France). All mutations but two were either nonsense, frameshift, or splice-site changes. The common NPHP6/CEP290 intronic mutation accounted for 43% (33/76) of all disease alleles. Twelve families did not carry this common intronic mutation. At least 10 out of them harboured two mutations expected to truncate the protein questioning the relevance of the assumption according to which the retinal-restricted phenotype in LCA patient could be due to a residual NPHP6/CEP290 activity. Finally, we show that all patients were affected with the cone-rod subtype of the disease whatever their NPHP6/CEP290 genotype.

Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons

“…Despite these differences, it is apparent that sensory cells are much more susceptible to mutations in CEP290 than other ciliary systems. Nonsense mutations of CEP290 result in Joubert syndrome, characterized by retinal degeneration, cerebellar vermis aplasia, and nephronophthisis, and Meckel syndrome, an autosomal recessive lethal condition characterized by CNS, kidney, and liver malformations (15,21,22,25). Missense mutations (such as those detected in LCA and the rd16 mice), however, appear to only affect sensory systems, resulting in retinal degeneration and olfactory dysfunction in both humans and mice, with no overt kidney or cerebellar defects.…”

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

“…Previous studies in LCA revealed the intronic CEP290 variant c.2991+1655A4G as the most frequent in the Caucasian population, explaining~12% of cases in Caucasian populations originating from North-West Europe. [13][14][15] In addition, the AIPL1 variant p.(W278*) in exon 6, a conspicuous cluster of CRB1 variants in exons 7 and 9, and the GUCY2D exon 12 variant p.(R768W) together may explain~14% of the cases. 16,17 Therefore, prescreening of these 5 exons potentially identifies 26% of the mutations, serving as a cost-and time-effective genotyping procedure for LCA.…”

Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration

“…CEP290 mutations have been described in up to 20% of cases of the devastating inherited blinding disease Leber congenital amaurosis (7,8) and in numerous cases of other more debilitating ciliopathies, such as Joubert syndrome (9-11), Senior-Løken syndrome (12), and Meckel-Gruber syndrome (13). How the many identified mutations in CEP290 contribute to these diverse pathologies remains unknown, and the protein's normal biological role has not been well characterized.…”