IDENTIFICATION OF THE GENE(S) RESPONSIBLE FOR ALAGILLE SYNDROME

Alagille综合征(AGS)是一种常染色体显性遗传病，其特征是 肝内胆汁淤积和心脏、眼睛和心脏的异常 脊椎骨，以及特有的面部外观。上一首 细胞遗传学缺失的罕见AGS患者的鉴定 允许将该基因定位到20p12。我们产生了一种细菌 临界区的人工克隆(BAC)重叠群和使用的荧光 亚显微肿瘤患者细胞的原位杂交 删除以将候选区域缩小到250 kb。在这个区域内 我们已经鉴定出JAG1，它是大鼠Jagged1的人类同源物，编码 Notch受体的配体。细胞-细胞锯齿状/凹槽相互作用是 已知对早期细胞命运的决定至关重要 发育，使其成为一种有吸引力的发育的候选基因 人类的紊乱。确定基因的完整外显子-内含子结构 JAG1允许对来自中国的DNA样本进行详细的突变分析 非缺失型AGS患者，发现三个移码突变，两个 剪接供体突变，以及一个突变取消了来自 改变后的等位基因。我们的结论是，AGS是由单倍性不足引起的 JAG1的同源性。

Alagille syndrome (AGS) is an autosomal dominant condition characterized by intrahepatic cholestasis and abnormalities of heart, eye, and vertebrae, as well as a characteristic facial appearance. Previous identification of rare AGS patients with cytogenetic deletions has allowed mapping of the gene to 20p12. We have generated a bacterial artificial clone (BAC) contig of the critical region and used fluorescent in situ hybridization (FISH) on cells from patients with submicroscopic deletions to narrow the candidate region to 250 kb. Within this region we have identified JAG1, the human homolog of rat Jagged1, which encodes a ligand for the Notch receptor. Cell-cell Jagged/Notch interactions are known to be critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon-intron structure of JAG1 allowed detailed mutational analysis of DNA samples from non-deletion AGS patients, revealing three frameshift mutations, two splice donor mutations, and one mutation abolishing RNA expression from the altered allele. We conclude that AGS is caused by haploinsufficiency of JAG1.