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.

Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.