title: A non-ancestral RPGR missense mutation in families with either recessive or semi-dominant X-linked retinitis pigmentosa.
abstract: Most X-linked diseases show a recessive pattern of inheritance in which female carriers are unaffected. In X-linked retinitis pigmentosa (XLRP), however, both recessive and semi-dominant inheritance patterns have been reported. We identified an Israeli family with semi-dominant XLRP due to a missense mutation (p.G275S) in the RPGR gene. The mutation was previously reported in two Danish families with recessive XLRP. Obligate carriers from the two Danish families had no visual complaints and normal to slightly reduced retinal function, while those from the Israeli family suffered from high myopia, low visual acuity, constricted visual fields, and severely reduced electroretinogram (ERG) amplitudes. The disease-related RPGR haplotype of the Israeli family was found to be different from the one found in the two Danish families, indicating that the mutation arose twice independently on different X-chromosome backgrounds. A series of genetic analyses excluded skewed X-inactivation pattern, chromosomal abnormalities, distorted RPGR expression level, and mutations in candidate genes as the cause for the differences in disease severity of female carriers. To the best of our knowledge, this is the first detailed analysis of an identical mutation causing either a recessive or a semi-dominant X-linked pattern of disease in different families. Our results indicate that an additional gene (or genes), linked to RPGR, modulate disease expression in severely affected carriers. These may be related to the high myopia concomitantly found in affected carriers from the Israeli family.
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Liliana
authors.initials: L
authors.lastname: Mizrahi-Meissonnier
authors.forename: Ruhama
authors.initials: R
authors.lastname: Neis
authors.forename: Shira
authors.initials: S
authors.lastname: Silverstein
authors.forename: István
authors.initials: I
authors.lastname: Magyar
authors.forename: Dvorah
authors.initials: D
authors.lastname: Abeliovich
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005799:Genes, Dominant; D005808:Genes, Recessive; D040181:Genetic Diseases, X-Linked; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D005136:Eye Proteins; C099929:RPGR protein, human