97th DOG Annual Meeting 1999
CLINICAL AND MOLECULAR GENETIC CHARACTERIZATION OF A NOVEL NONSENSE MUTATION (E302X) OF THE PERIPHERIN/RDS GENE IN PSEUDOVITELLIFORM MACULAR DEGENERATION
U. Schmidt-Erfurth, A. Ehrenfeld, I. Barbazetto, H. Laqua, A. Gal
A genetic component in the pathogenesis of macular dystrophies is being discussed. However, to date only a few specific mutations have been identified which showed clear association with a defined clinical pathology. A complete clinical work-up and molecular genetic screening of the peripherin/ RDS gene was performed on an unselected population of patients with pseudovitelliform macular degeneration (PMD).
Patients and method: Patients with typical vitelliform lipofuscin plaques underwent a functional (ETDRS-visual acuity test, contrast sensitivity, microperimetry), angiographic (FLA and ICG) and electrophysiological (ERG/EOG) evaluation of the pheno-type. Genetic analysis was done by SSCP analysis and direct sequencing.
Results: 53 patients were examined. Mean visual acuity was 20/80, contrast sensitivity 30, a relative scotoma of 20,5 dB was present, and an early masking/late leakage appearance was seen by FLA and ICG. EOG and ERG were normal. In one patient, we identified a heterozygous G to T transversion of the 3rd nucleotide of codon 302 of the peripherin/RDS gene which changed the triplet GAG (encoding glutamic acid) to GAT (stop). Therefore this mutation predicts a premature termination of protein translation and a truncated polypeptide with the last 44 amino acids at the carboxyl terminus missing. The clinical phenotype with lipofuscin deposits, moderate functional loss and intact ERG/EOG was clearly consistent with the classic features of PMD.
Conclusion: This study is based on the largest unselected patient collection with PMD ever systematically evaluated in clinical and genetic respect. The incidence of a peripherin/RDS gene mutation was as low as 2%. The nonsense mutation described by us results most likely in an afunctional protein (haplo-insufficiency). In addition to the other mutations identified so far in the peripherin/RDS gene in cases of PMD, this novel mutation provides additional evidence for genetic heterogeneity of macular dystrophies.
University Eye Hospital Luebeck
Institute of Human Genetics, University Hospital of Hamburg-Eppendorf