Retinal dystrophies (DR) belong to a group of genetic diseases that show a mendelian pattern of inheritance, cause progressive retinal degeneration and are highly heterogeneous at the clinical and genetic level. Among them, retinitis pigmentosa is the most prevalent (RP) (1:4000). More than 50 RP and 100 DR genes are known, which overall only explain around 65% of the cases. At present, the molecular diagnosis by direct molecular screening is unviable due to the high number of candidate genes and exons to be studied and the costs and time involved in sequencing all these regions. Recently, we have provided a DNA chip to approach to approach the familial molecular diagnosis of RD. The chip allows to perform a highthroughput cosegregation analysis of 700 SNP markers closely linked to the candidate genes. This is a new highly efficient and robust tool to establish a priority list for the genes to be studied.

As the second aim of our research we are attempting to identifiy novel DR genes and to perform the functional charaterization to unveil the molecular basis of their pathogenicity. In the past we did characterise three RP genes RP using linkage analysis: ABCA4, CERKL and PROM1. Recently, we have started new searches in RD families that have more than one affected member using our cosegregation chip and massive massive DNA sequencing.

Finally, our last aim is to perform a functional study of CERKL, using biochemical, bioinformatic, molecular and cellular approaches. We have shown that a high number of CERKL transcripts are produced in different tissues of human and mouse, particularly in the retina. This unexpected transcriptional heterogeneity is due to additional CERKL promoters located downstream the conventional promoter combined with a high number of RNA isoforms generated by alternative splicing. This transcripcional heterogeneity opens new avenues to study the CERKL genotype/phenotype correlations. We have construted a murine model of the recessive forms of RP (knockdown CERKL -/-) and have characterised this model at the the electrophysiological, cellular and morphological level. Finally, we have just initiated the study of new animal models of RP to identify the molecular basis of CERKL pathogenicity and to highlight the effective therapeutical targets.