Johnson D W, Berg J N, Baldwin M A, Gallione C J, Marondel I, Yoon S J, Stenzel T T, Speer M, Pericak-Vance M A, Diamond A, Guttmacher A E, Jackson C E, Attisano L, Kucherlapati R, Porteous M E, Marchuk D A
Department of Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nat Genet. 1996 Jun;13(2):189-95. doi: 10.1038/ng0696-189.
Hereditary haemorrhagic telangiectasia, or Osler-Rendu-Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38-Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALK1), a member of the serine-threonine kinase receptor family expressed in endothelium. We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12. Our data suggest a critical role for ALK1 in the control of blood vessel development or repair.
遗传性出血性毛细血管扩张症，即奥斯勒-伦杜-韦伯（ORW）综合征，是一种常染色体显性血管发育异常疾病。到目前为止，已证实ORW存在两个基因座。连锁研究确定了9号染色体长臂3区的一个ORW基因座；随后内皮糖蛋白被鉴定为ORW1基因。第二个基因座，命名为ORW2，被定位到12号染色体。在此我们报告一个新的4厘摩的ORW2区间，它与之前定义的区间均不重叠。一个1.38兆碱基对的酵母人工染色体重叠群覆盖了整个区间。它包含激活素受体样激酶1基因（ACVRLK1或ALK1），这是丝氨酸-苏氨酸激酶受体家族的一个成员，在内皮细胞中表达。我们在那些显示ORW表型与12号染色体连锁的家族中报告了ALK1基因编码序列的三个突变。我们的数据表明ALK1在控制血管发育或修复中起关键作用。
