Deficiency of rds/peripherin causes photoreceptor death in mouse models ofdigenic and dominant retinitis pigmentosa

Retinitis pigmentosa (RP) is a group of inherited blinding diseases caused by mutations in multiple genes including RDS. RDS encodes rds/peripherin (r ds), a 36-kDa glycoprotein in the rims of rod and cone outer-segment (OS) d iscs. Rom1 is related to rds with similar membrane topology and the identic al distribution in OS. In contrast to RDS, no mutations in ROM1 alone have been associated with retinal disease. However, an unusual digenic form of R P has been described. Affected individuals in several families were doubly heterozygous for a mutation in RDS causing a leucine 185 to proline substit ution in rds (L185P) and a null mutation in ROM1. Neither mutation alone ca used clinical abnormalities. Here, we generated transgenic/knockout mice th at duplicate the amino acid substitutions and predicted levels of rds and r om1 in patients with RDS-mediated digenic and dominant RP. Photoreceptor de generation in the mouse model of digenic RP was faster than in the wild-typ e and monogenic controls by histological, electroretinographic, and biochem ical analysis. We observed a positive correlation between the rate of photo receptor loss and the extent of OS disorganization in mice of several genot ypes. Photoreceptor degeneration in RDS-mediated RP appears to be caused by a simple deficiency of rds and rom1. The critical threshold for the combin ed abundance of rds and rom1 is approximate to 60% of wild type, Below this value, the extent of OS disorganization results in clinically significant photoreceptor degeneration.