Purpose: To understand the pathophysiology of human retinal degenerations caused by mutations in the peripherin/RDS gene.
Methods: Three families with autosomal dominant retinal degeneration were found to have mutations in the peripherin/RDS gene. There were two frameshift mutations: a 1-base pair (bp) insertion at codon 32 and a 2-bp deletion at codon 193. For these mutations, the predicted proteins would be truncated by 303 and 131 amino acids, respectively. The third mutation would result in an 8-bp substitution for five nucleotides involving codons 67-69 and would be predicted to disrupt the second transmembrane domain of the protein. Heterozygotes were examined clinically and with rod and cone perimetry, dark adaptometry, and rod- and cone-isolated electroretinograms (ERGs).
Results: Rod and cone sensitivity losses were present with perimetric testing in most patients; patients with advanced disease in all three families showed more pericentral than peripheral field dysfunction. The kinetics of dark adaptation were abnormal in all patients. Rod and cone ERG a-waves were normal in maximum amplitude in three younger patients but were reduced in all others; phototransduction was normal in most patients. There was equal loss of rod and cone a-wave amplitudes and equal elevation of rod and cone thresholds.
Conclusions: Heterozygotes with these different peripherin/RDS gene mutations showed variation in clinical presentation but a similar pattern of receptor abnormalities. Results of visual function tests were consistent with a normal amount of rod and cone outer segment membrane in early disease, progressing to reduced outer segments at later stages. There was an equal effect on rod and cone photoreceptor function at all stages of disease. This functional phenotype may represent the human analogue of the rds/+ mouse.