Analyzing And Mapping The Disease Gene For Two Hereditary Nonsyndromic Retinitis Pigmentosa Families

Backgrounds:Visual loss is a common sensory disorder.Retinitis pigmentosa(RP)is one of the most common ophthalmopathy,with permanent visual loss or even blindness as the ultimate consequence. Sixty-five percent of inherited RP is nonsyndromic.High degree of genetic and clinical heterogeneity makes RP very complex.The mode of heritance can include autosomal dominant,autosomal recessive,X-linked, digenic and sporadic.About 60 percent of the nonsyndromic retinitis pigmentosa(NSRP)patients are caused by unknown genes and mutations.There are more than 400,000 RP patients in China,and the number keeps increasing year by year.Unfortunately there is still no sound treatment.Most patients lose the ability to work as usual,which brings a heavy financial and mental burden to society and their families.Objective:To establish hereditary NSRP genetic diagnosis system by analyzing disease incidence and characteristics of the clinical manifestations,and to provide genetic diagnosis,genetic counseling and prenatal diagnosis for the hereditary NSRP families.Methods:Hereditary NSRP genetic diagnosis system was established by improvement of clinical examination of RP patients, analyzing the different characteristics and epidemiology of NSRP genes. Polymerase chain reaction(PCR),direct DNA sequencing,genome scan and linkage analysis methods were used to analyze the known genes and published loci of the 2 NSRP families we collected.Results:Two novel synonymous mutations(c.2166A＞G and c.3396C＞T)of exon open reading frame 15(ORF15),and four known polymorphisms of retinitis pigmentosa GTPase regulator(RPGR)gene were detected in the proband of the X-linked recessive retinitis pigmentosa family(family 1);One novel heterozygous intronic nucleotide change(c.1439 +43 G＞A)of IMP Dehydrogenase 1 gene (IMPDH1)and sixteen known polymorphisms of other 12 genes(RHO, RDS,PRPF31,IMPDH1,RP1(exon4),GUCAIB,ROM1, PRPF8(exon43),PRPF3(exon11),NRL,FSCN2,CRX and TOPORS) were detected in the proband of the autosomal dominant retinitis pigmentosa family(family 2).Then genome scan and linkage analysis were performed on family 2.The result suggested that the family's disease was not inherited in X-linked manner,and the maximum two-point LOD score 1.16 was obtained at D9S 1846.Haplotype analysis localized disease locus to a 12.9 cM critical region between microsatellite markers D9S285 and D9S1817,in which RP31(D9S285-D9S1817-D9S1874) is included.Conclusion:1.The NSRP genetic diagnosis system was established based on the epidemiology of the NSRP genes and the NSRP genes with characterized clinical manifestation.2.According to the system,gene mutation analysis was performed on the most common XLRP gene -RPGR,no pathogenic mutation was found in family 1,so the genetic etiology of the family remained unknown.3.According to the system,13 known ADRP genes mutation analysis was performed,no pathogenic mutation was found in family 2. Genome scan and linkage analysis of family 2 suggested that pathogenic gene might be in the chromosome 9p22.3-9p13.2,between micro satellite markers D9S285 and D9S1817(a 12.9 cM critical region).4.RP is a kind of disease with a high degree of heterogeneity.