Yuan Z R, Kohsaka T, Ikegaya T, Suzuki T, Okano S, Abe J, Kobayashi N, Yamada M
National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154, Japan and National Children's Hospital, Tokyo, Japan.
Hum Mol Genet. 1998 Sep;7(9):1363-9. doi: 10.1093/hmg/7.9.1363.
Alagille syndrome (AGS) is an autosomal dominant disease characterized by five major abnormalities in the liver, heart, face, vertebrae and eye. The responsible gene has been recently identified as the human Jagged 1 (JAG1) gene, which encodes a ligand for the Notch receptor. We analyzed the JAG1 gene in eight AGS families, including affected and unaffected individuals, at the genomic DNA level, mainly by single-strand conformational polymorphism (SSCP) and DNA sequencing analysis. Four categories of mutations were identified: (i) four frameshift mutations in exons 9, 22, 24 and 26 were exhibited respectively in affected individuals of four AGS families, which resulted in moving the translational frame of JAG1; (ii) one nonsense mutation, a 1 bp substitution in exon 5 of the EGF-like repeat domain, was detected in two unrelated AGS families, which altered codon 235 from arginine to stop; (iii) one acceptor splice site mutation of exon 5 was revealed in a sporadic patient; and (iv) a 1.3 Mb deletion, which included the entire JAG1 gene, was found in another patient. Our results further demonstrate that AGS is a dominant disease and suggest that the JAG1 gene exerts a fundamental role in regulating genes involved in development.
阿拉吉尔综合征（AGS）是一种常染色体显性疾病，其特征为肝脏、心脏、面部、脊椎和眼睛出现五大异常。最近已确定致病基因为人锯齿状蛋白1（JAG1）基因，该基因编码Notch受体的一种配体。我们主要通过单链构象多态性（SSCP）和DNA测序分析，在基因组DNA水平上分析了八个AGS家族中的JAG1基因，包括患病个体和未患病个体。共鉴定出四类突变：（i）四个AGS家族的患病个体中分别在外显子9、22、24和26出现四个移码突变，导致JAG1的翻译框架移动；（ii）在两个不相关的AGS家族中检测到一个无义突变，即表皮生长因子样重复结构域外显子5中的1个碱基替换，该突变将密码子235由精氨酸变为终止密码子；（iii）在一名散发性患者中发现外显子5的一个剪接受体位点突变；（iv）在另一名患者中发现一个1.3 Mb的缺失，该缺失包含整个JAG1基因。我们的结果进一步证明AGS是一种显性疾病，并表明JAG1基因在调控参与发育的基因方面发挥着重要作用。
