A variant form of Oguchi disease mapped to 13q34 associated withpartial deletion of GRK1 gene

摘要

Purpose: The purpose of this paper is to map the locus for a variantform of Oguchi disease in a Pakistani family and to identify thecausative mutation.Methods: Family 61029 was ascertained in the Punjab province ofPakistan. It includes three 13- to 19-year-old patients with nightblindness and 12 unaffected family members. A complete ophthalmologicalexamination including fundus photography and electroretinography (ERG)was performed on each family member. A genome-wide scan was performedusing microsatellite markers at about 10 cM intervals, and two-point lodscores were calculated. Polymerase chain reaction (PCR) cycledideoxynucleotide sequencing was used to screen candidate genes insidethe linked region for mutations and to delineate the deletion. MultiplexPCR and long template PCR were used to detect deletions and to definethe size of deletions. Evaluation of fundus changes and ERG, lod scoreestimation, and identification of a mutation in the GRK1 gene werecarried out.Results: All patients had night blindness since early childhood.Irregular coarse pigmentation was observed in the peripheral retina ofeach patient. The fundus appearance before and after 4 h of darkadaptation was similar except that the peripheral retinal pigmentarychanges were slightly less evident after extended dark adaptation.Minimal or no rod function with normal cone function on ERG recordingswere detected in all three affected members. The rod showed slowrecovery to nearly normal amplitude after 4 h in the dark ERG in oneindividual but not in two other patients. A genome-wide scan showedlinkage only to D13S285. Fine mapping defined a region from D13S1315 to13qter, with a lod score of 2.89 at θ=0 shown by D13S285 and 2.90at θ=0 by the D13S261-D13S285-D13S1295-D13S293 haplotype. Analysisof the GRK1 gene, which is included in this interval, identified ac.827+623_883del mutation. This intragenic deletion cosegregates withthe disease in the family and is only homozygous in affectedindividuals. This mutation was not detected in 96 controls.Conclusions: The retinal disease in the family reported here hasseveral features differing from typical Oguchi disease, including anatypical Mizuo-Nakamura phenomenon and a non-recordable rod ERG evenafter 4 h of dark adaptation. Normal visual acuity, normal caliber ofretinal blood vessels, and normal cone response on ERG recording suggestretinal dysfunction rather than degeneration (i.e., a variant form ofOguchi disease but unlikely to be retinitis pigmentosa). The disease inthe Pakistani family localizes to 13q34 and is caused by a noveldeletion including Exon 3 of the GRK1 gene.