Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1
Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1
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DOI：
10.1038/ng0797-243
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发表时间：
1997-07-01
期刊：
影响因子：
30.8
通讯作者：
Spinner, NB
中科院分区：
文献类型：
--
作者：
Li, LH;Krantz, ID;Spinner, NB
阿拉杰里综合征是一种常染色体显性遗传病，其特征为肝脏、心脏、骨骼、眼睛、面部发育异常，肾脏异常较少见。对许多有细胞遗传学缺失或重排的患者进行分析后，将该基因定位在20p12号染色体上，不过在患者中发现缺失的比例相对较小（<7%）。我们已将人锯齿蛋白1基因（JAG1）定位在20p12内的阿拉杰里综合征关键区域，该基因编码一种对发育具有重要作用的Notch跨膜受体的配体。Notch细胞间信号通路已被证明在无脊椎动物和脊椎动物的发育过程中调节细胞命运决定。我们在来自四个阿拉杰里综合征家庭的JAG1中发现了四种不同的编码突变，这证明它是阿拉杰里综合征的致病基因。所有这四种突变都位于该基因的保守区域内，并导致翻译移码，从而使蛋白质产物发生重大改变。细胞遗传学可检测到包括JAG1在内的缺失的患者患有阿拉杰里综合征，这支持了该基因单倍体不足是导致阿拉杰里综合征表型的机制之一这一假说。
Alagille syndrome is an autosomal dominant disorder characterized by abnormal development of liver, heart, skeleton, eye, face and, less frequently, kidney. Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%). We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12. The Notch intercellular signalling pathway has been shown to mediate cell fate decisions during development in invertebrates and vertebrates. We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome. All four mutations lie within conserved regions of the gene and cause translational frameshifts, resulting in gross alterations of the protein product. Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome, supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagille syndrome phenotype.