A novel de novo frameshift mutation of RPGR ORF15 isassociated with X-linked retinitis pigmentosa in a Chinese family

摘要

Purpose: To identify the genetic basis of disease in a Chinesefamily with retinitis pigmentosa (RP).Methods: Linkage analysis was performed for 15 family membersin the RP family using microsatellite markers flanking candidate geneticloci for known autosomal dominant RP (adRP) and markers covering theentire X chromosome by every 10 cM. To screen for a mutation causing RP,PCR and DNA sequence analyses of the complete coding region (includingORF15) and exon-intron boundaries of the retinitis pigmentosa GTPaseregulator (RPGR) gene associated with X-linked RP (xlRP) were carriedout for the proband in the RP family. After the mutation was identified,direct DNA sequence analysis was preformed for all 15 family members and101 controls to determine whether the mutation co-segregated with RP inthe family and whether it was present or absent in the controls.Results: Linkage analysis excluded all known adRP loci.However, positive linkage was identified with two markers on the Xchromosome, DXS993 and DXS1068, where the RPGR gene islocated. Direct DNA sequence analysis revealed a hemizygous mutation,g.ORF15+1166delA (c.2919delA), in affected males. The deletion resultsin a frameshift leading to early termination of RPGR. Theg.ORF15+1166delA mutation arose de novo and co-segregated with all malepatients, but was not present in normal family members and 101 controls.The clinical features of the mutation carriers showed intrafamilialvariability.Conclusions: The novel g.ORF15+1166delA mutation of RPGR causesX-linked RP in a four generation Chinese family. The deletion arose denovo. An interesting feature of mutation g.ORF15+1166delA is that it wasassociated with RP in all hemizygous males and four of five heterozygousfemale carriers in the Chinese family. These results revealed thebroader xlRP genotypic and phenotypic spectrum of RPGR mutations.