Zhang Qingjiong, Zulfiqar Fareeha, Riazuddin S Amer, Xiao Xueshan, Ahmad Zahoor, Riazuddin Sheikh, Hejtmancik J Fielding
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1860, USA.
Mol Vis. 2004 Nov 17;10:884-9.
To map the locus for autosomal recessive retinitis pigmentosa in a large Pakistani family and to determine the causative mutation.
A large family with multiple individuals affected by autosomal recessive retinitis pigmentosa was ascertained in the Punjab province 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 recessive retinitis pigmentosa loci, a genome wide scan was performed using microsatellite markers at about 10 cM intervals. Two point lod scores were calculated and haplotypes were analyzed in order to define disease locus. Bidirectional dideoxynucleotide sequencing was used to screen for mutations in candidate genes.
In the genome wide scan, autosomal recessive retinitis pigmentosa in this Pakistani family showed linkage to an 11.7 cM region of chromosome 4p12 between D4S405 and D4S1592 with a maximum lod score of 2.90 with D4S405 at theta;=0.01 Sequence analysis of CNGA1 identified a 2 bp deletion in exon 8: c.626_627delTA resulting in a frameshift, p.Ser209fsX26 in the translated protein. This mutation results in deletion of the COOH terminal 482 of 690 total amino acids in CNGA1 and their replacement by 25 novel amino acids before a premature termination. The mutation is found in a homozygous state in all 7 affected individuals and was heterozygous in all 15 unaffected family members examined. The mutant allele of CNGA1 itself shows linkage to the disease with maximum lod score of 4.43 at theta;=0.
The autosomal recessive retinitis pigmentosa in this family is caused by a mutation in CNGA1 gene. To our knowledge, this is the first report in which both linkage analysis and identification of a mutation support CNGA1 as a cause for autosomal recessive retinitis pigmentosa.
在一个庞大的巴基斯坦家族中定位常染色体隐性遗传性视网膜色素变性的基因座，并确定致病突变。
作为巴基斯坦拉合尔的真纳研究生医学中心（CEMB）与美国国立眼科研究所（NEI）之间正在进行的一个旨在确定眼病遗传病因的项目的一部分，在巴基斯坦旁遮普省确定了一个有多个个体患常染色体隐性遗传性视网膜色素变性的大家族。在对先前确定的常染色体隐性遗传性视网膜色素变性基因座进行初步分析之后，使用间距约为10厘摩（cM）的微卫星标记进行全基因组扫描。计算两点连锁分析计分，并分析单倍型以确定疾病基因座。采用双向双脱氧核苷酸测序法筛选候选基因中的突变。
在全基因组扫描中，这个巴基斯坦家族的常染色体隐性遗传性视网膜色素变性与4号染色体p12区11.7厘摩区域（位于D4S405和D4S1592之间）连锁，在θ=0.01时与D4S405的最大连锁分析计分是2.90。对环核苷酸门控离子通道1（CNGA1）基因的序列分析确定外显子8有一个2碱基对缺失：c.626_627delTA，导致移码突变，使翻译后的蛋白质中出现p.Ser209fsX26。该突变导致CNGA1总共690个氨基酸中的羧基末端482个氨基酸缺失，并在提前终止前被25个新氨基酸取代。在所有7名患病个体中均发现该突变呈纯合状态，在所有接受检测的15名未患病家庭成员中呈杂合状态。CNGA1基因的突变等位基因本身与疾病连锁，在θ=0时的最大连锁分析计分是4.43。
这个家族的常染色体隐性遗传性视网膜色素变性是由CNGA1基因突变引起的。据我们所知，这是第一份通过连锁分析和突变鉴定均支持CNGA1基因是常染色体隐性遗传性视网膜色素变性病因的报告。
