Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis

Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal r ecessive condition responsible for congenital blindness or greatly impaired vision since birth. So far, six LCA loci have been mapped but only 4 out o f 6 genes have been identified. A genome-wide screen for homozygosity was c onducted in seven consanguineous families unlinked to any of the six LCA lo ci. Evidence for homozygosity was found in two of these seven families at t he 14q11 chromosomal region. Two retinal specific candidate genes were know n to map to this region, namely the neural retina leucine zipper (NRL) and the retinitis pigmentosa GTPase regulator interacting protein (RPGRIP1). No mutation of the NRL gene was found in any of the two families. Thus, we de termined the complete exon-intron structure of the RPGRIP1 gene. RPGRIP1 en compasses 24 coding exons, nine of which are first described here with thei r corresponding exon-intron boundaries. The screening of the gene in the tw o families consistent with linkage to chromosome 14q11 allowed the identifi cation of a homozygous null mutation and a homozygous missense mutation, re spectively. Further screening of LCA patients unlinked to any of the four a lready identified LCA genes (n=86) identified seven additional mutations in six of them. In total, eight distinct mutations (5 out of 8 truncating) in 8/93 patients were found. So far this gene accounts for eight out of 142 L CA cases in our series (5.6%).