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

Purpose: The purpose of this paper is to map the locus for a variant form of Oguchi disease in a Pakistani family and to identify the causative mutation. Methods: Family 61029 was ascertained in the Punjab province of Pakistan. It includes three 13- to 19-year-old patients with night blindness and 12 unaffected family members. A complete ophthalmological examination including fundus photography and electroretinography (ERG) was performed on each family member. A genome-wide scan was performed using microsatellite markers at about 10 cM intervals, and two-point lod scores were calculated. Polymerase chain reaction (PCR) cycle dideoxynucleotide sequencing was used to screen candidate genes inside the linked region for mutations and to delineate the deletion. Multiplex PCR and long template PCR were used to detect deletions and to define the size of deletions. Evaluation of fundus changes and ERG, lod score estimation, and identification of a mutation in the GRK1 gene were carried out. Results: All patients had night blindness since early childhood. Irregular coarse pigmentation was observed in the peripheral retina of each patient. The fundus appearance before and after 4 h of dark adaptation was similar except that the peripheral retinal pigmentary changes were slightly less evident after extended dark adaptation. Minimal or no rod function with normal cone function on ERG recordings were detected in all three affected members. The rod showed slow recovery to nearly normal amplitude after 4 h in the dark ERG in one individual but not in two other patients. A genome-wide scan showed linkage only to D13S285. Fine mapping defined a region from D13S1315 to 13qter, with a lod score of 2.89 at theta=0 shown by D13S285 and 2.90 at theta=0 by the D13S261-D13S285-D13S1295-D13S293 haplotype. Analysis of the GRK1 gene, which is included in this interval, identified a c.827+623_883del mutation. This intragenic deletion cosegregates with the disease in the family and is only homozygous in affected individuals. This mutation was not detected in 96 controls. Conclusions: The retinal disease in the family reported here has several features differing from typical Oguchi disease, including an atypical Mizuo-Nakamura phenomenon and a non-recordable rod ERG even after 4 h of dark adaptation. Normal visual acuity, normal caliber of retinal blood vessels, and normal cone response on ERG recording suggest retinal dysfunction rather than degeneration (i.e., a variant form of Oguchi disease but unlikely to be retinitis pigmentosa). The disease in the Pakistani family localizes to 13q34 and is caused by a novel deletion including Exon 3 of the GRK1 gene.