title: RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa.
abstract: We determined the mutation spectrum of the RP2 and RPGR genes in patients with X-linked retinitis pigmentosa (XLRP) and searched for correlations between categories of mutation and severity of disease. We screened 187 unrelated male patients for mutations, including 135 with a prior clinical diagnosis of XLRP, 11 with probable XLRP, 30 isolate cases suspected of having XLRP, and 11 with cone-rod degeneration. Mutation screening was performed by single-strand conformation analysis and by sequencing of all RP2 exons and RPGR exons 1-14, ORF15, and 15a. The refractive error, visual acuity, final dark-adapted threshold, visual field area, and 30-Hz cone electroretinogram (ERG) amplitude were measured in each patient. Among the 187 patients, we found 10 mutations in RP2, 2 of which are novel, and 80 mutations in RPGR, 41 of which are novel; 66% of the RPGR mutations were within ORF15. Among the 135 with a prior clinical diagnosis of XLRP, mutations in the RP2 and RPGR genes were found in 9 of 135 (6.7%) and 98 of 135 (72.6%), respectively, for a total of 79% of patients. Patients with RP2 mutations had, on average, lower visual acuity but similar visual field area, final dark-adapted threshold, and 30-Hz ERG amplitude compared with those with RPGR mutations. Among patients with RPGR mutations, those with ORF15 mutations had, on average, a significantly larger visual field area and a borderline larger ERG amplitude than did patients with RPGR mutations in exons 1-14. Among patients with ORF15 mutations, regression analyses showed that the final dark-adapted threshold became lower (i.e., closer to normal) and that the 30-Hz ERG amplitude increased as the length of the wild-type ORF15 amino acid sequence increased. Furthermore, as the length of the abnormal amino acid sequence following ORF15 frameshift mutations increased, the severity of disease increased.
authors.affiliation: Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sandberg
authors.forename: Vivian W
authors.initials: VW
authors.lastname: Rabe
authors.forename: Melissa
authors.initials: M
authors.lastname: Stillberger
authors.forename: Thaddeus P
authors.initials: TP
authors.lastname: Dryja
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Berson
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics*; D004252:DNA Mutational Analysis; D003623:Dark Adaptation / Q000502:physiology; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D019204:GTP-Binding Proteins; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000503:physiopathology*; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology
chemical_list: D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C072178:RP2 protein, human; C099929:RPGR protein, human; D019204:GTP-Binding Proteins