Autosomal recessive retinitis pigmentosa in a Pakistani familymapped to CNGA1 with identification of a novel mutation

[摘要] Purpose: To map the locus for autosomal recessive retinitispigmentosa in a large Pakistani family and to determine the causativemutation.Methods: A large family with multiple individuals affected byautosomal recessive retinitis pigmentosa was ascertained in the Punjabprovince of Pakistan as part of an ongoing project between the CEMB,Lahore, Pakistan and the NEI to identify genetic causes of eye diseases.After initial analysis of previously identified autosomal recessiveretinitis pigmentosa loci, a genome wide scan was performed usingmicrosatellite markers at about 10 cM intervals. Two point lod scoreswere calculated and haplotypes were analyzed in order to define diseaselocus. Bidirectional dideoxynucleotide sequencing was used to screen formutations in candidate genes.Results: In the genome wide scan, autosomal recessive retinitispigmentosa in this Pakistani family showed linkage to an 11.7 cM regionof chromosome 4p12 between D4S405 and D4S1592 with a maximum lod scoreof 2.90 with D4S405 at θ=0.01 Sequence analysis of CNGA1 identifieda 2 bp deletion in exon 8: c.626_627delTA resulting in a frameshift,p.Ser209fsX26 in the translated protein. This mutation results indeletion of the COOH terminal 482 of 690 total amino acids in CNGA1 andtheir replacement by 25 novel amino acids before a prematuretermination. The mutation is found in a homozygous state in all 7affected individuals and was heterozygous in all 15 unaffected familymembers examined. The mutant allele of CNGA1 itself shows linkage to thedisease with maximum lod score of 4.43 at θ=0.Conclusions: The autosomal recessive retinitis pigmentosa in thisfamily is caused by a mutation in CNGA1 gene. To our knowledge, this isthe first report in which both linkage analysis and identification of amutation support CNGA1 as a cause for autosomal recessive retinitispigmentosa.

[学科分类] 生物化学/生物物理