Positional cloning of the gene causing Dyschromatosis Symmetrica Hereditaria

对称遗传性色素沉着症（DSH）是一种常染色体显性色素遗传病，由富山于1910年首次报道。它的特点是手背和脚背上出现各种大小的色素沉着和色素沉着的斑点。对于DSH位点，我们利用343个微卫星标记进行了全基因组扫描，并对3个DSH家族进行了连锁分析和单倍型分析，结果表明，DSH的基因位于约500kb的区间，近端由IL6R基因结合，远端由KCNN3基因结合，位于染色体1q21.3上。在这两个基因之间，有7个基因已在NCBI网站的Entrez Map View上被绘制出来。采用SSCP技术对家谱1、2、3和家谱4各4例患者进行了筛选，结果显示，通过rna特异性腺苷脱氨酶（The RNA-specific adenosine deaminase， DSRAD）基因的PCR片段杂交得到突变异双链。对PCR产物进行直接序列分析，结果表明它们分别与1、2、3和4家系R474X、L923P、K952X和F11655突变为杂合子。导致DSH的突变已经在编码DSRAD的基因中被确定为疾病基因。

Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary disorder, first reported by Toyama in 1910. It is characterized by a mixture of hypopigmented and hyperpigmented macules of various sizes on the backs of the hands and feet. To DSH locus, we tried an entire genome-wide scan using 343 microsatellite markers for linkage analysis and haplotype analysis was carried out in the three families with DSH, and the results suggested that the gene responsible for DSH lies in the interval of approximately 500kb which was bound proximally by the IL6R gene and distally by the KCNN3 gene at chromosome 1q21.3. Between those two genes, seven genes have been mapped on the Entrez Map View, NCBI web site. Four affected individuals from each of Pedigrees 1,2 and 3,and of Pedigree 4 were screened by SSCP, which revealed mutant heteroduplexes made by hybridizing PCR fragments of The RNA-specific adenosine deaminase (DSRAD) genes. Direct sequence analysis of the PCR products showed that they were heterozygous for mutations of R474X, L923P, K952X and F11655 in Pedigrees 1,2,3 and 4,respectively. The mutations involved in causing DSH have been identified in the gene that encodes DSRAD as the disease gene.