DEFECTIVE SUBUNIT ASSEMBLY UNDERLIES A DIGENIC FORM OF RETINITIS-PIGMENTOSA LINKED TO MUTATIONS IN PERIPHERIN RDS AND ROM-1

Retinitis pigmentosa (RP) is a group of progressive retinal dystrophie s that include the most common hereditary degenerative diseases affect ing the retina. Although most disease phenotypes appear to result from defects at single genetic loci (monogenic), at least one instance of RP appears to require a coinheritance of defects in the unlinked perip herin/rds and rom-l alleles (digenic), which encode the polypeptide su bunits of an oligomeric transmembrane protein complex present at photo receptor outer segment disc rims. Sedimentation velocity analysis was performed upon the affected gene products expressed heterologously in COS-I cells to examine the assembly of the subunit polypeptides. The r esults indicate that the missense peripherin/rds mutant, L185P, which segregates with instances of digenically inherited RP, is conditionall y defective with respect to its subunit assembly. Unlike wild-type per ipherin/rds, the L185P mutant does not form native-like homotetramers on its own: however the L185P mutant can assemble with wild-type rom-l to form a structurally normal heterotetrameric complex. These finding s provide a novel molecular-based rationale for the unusual digenic di sease inheritance pattern and offer insight into regions of peripherin /rds and rom-l, which contribute to subunit-subunit Interactions.