Mutations in the Gene for the B-Subunit of Rod Photoreceptor Cgmp-Specific Phosphodiesterase (PDEB) in Patients with Retinal Dystrophies and Dysfunctions
Rod photoreceptor cGMP-specific phosphodiesterase (PDE) is a key enzyme of the phototransduction cascade. Mutations in the gene encoding the β-subunit of PDE (βPDE) have been implicated in two distinct human retinal disorders; autosomal recessive retinitis pigmentosa (arRP) and autosomal dominant congenital stationary night blindness (adCSNB).
We examined the βPDE gene in 101 unrelated patients with arRP from Germany for sequence changes by single strand conformation polymorphism analysis. Band shifts were detected in 17 different gene fragments amplified by polymerase chain reaction. Direct sequencing revealed 11 single base substitutions that were considered being most likely polymorphisms. Of the remaining six, and most likely disease related exonic mutations, three (225C→T/Arg74Cys, 226insC, and 660T→C/Tyr219His) have been found in patients with only one (heterozygous) βPDE-mutation identified so far. In two patients, both βPDE-alleles carried potentially pathogenic mutations; one patient was homozygote for the 1585T→C/Leu527Pro change while the other one was a compound hetrrozygote for 897C→T/Gln298stop and 2565C→G/Leu854Val. This latter patient, a 19-year-old female, presented with typical clinical, electrophysiological, and psychophysical symptoms of a rod-cone degeneration.
We have recently described a large multigeneration Danish pedigree with adCSNB, in which the photoreceptor dysfunction was cosegregating with a heterozygous His258Asn mutation of the βPDE gene. Here we report two further Danish pedigrees with adCSNB and the His258Asn mutation. Both families were shown to be unrelated to the original pedigree for (at least the last) 6 generations. Nevertheless, genotyping for 11 different intragenic DNA polymorphisms revealed that night blind subjects in the three families shared the same βPDE haplotype suggesting that the His258Asn allele originated from a common ancestor. Assuming that the three families were linked in the seventh generation, a maximum lod score of 28.615 at theta = 0.00 was obtained for the linkage relationship between the loci for adCSNB and βPDE. These data provide strong support for the hypothesis that the mutant βPDE is responsible for CSNB in this family, i.e. that the molecular defect is in the phototransduction cascade and at the photoreceptor level.
KeywordsRetinitis Pigmentosa Night Blindness Retinal Dystrophy Single Strand Conformation Polymorphism Analysis Heterozygous Missense Mutation
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