Oda T, Elkahloun A G, Pike B L, Okajima K, Krantz I D, Genin A, Piccoli D A, Meltzer P S, Spinner N B, Collins F S, Chandrasekharappa S C
Laboratory of Gene Transfer, National Human Genome Research Institutes of Health, Bethesda, Maryland 20892-4442, USA.
Nat Genet. 1997 Jul;16(3):235-42. doi: 10.1038/ng0797-235.
Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by intrahepatic cholestasis and abnormalities of heart, eye and vertebrae, as well as a characteristic facial appearance. Identification of rare AGS patients with cytogenetic deletions has allowed mapping of the gene of 20p12. We have generated a cloned contig of the critical region and used fluorescent in situ hybridization on cells from patients with submicroscopic deletions to narrow the candidate region to only 250 kb. Within this region we identified JAG1, the human homologue 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 frame-shift 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.
阿拉吉耶综合征（AGS）是一种常染色体显性疾病，其特征为肝内胆汁淤积、心脏、眼睛和脊椎异常以及独特的面部外观。对罕见的细胞遗传学缺失AGS患者的鉴定使得20p12基因得以定位。我们构建了关键区域的克隆重叠群，并对亚显微缺失患者的细胞进行荧光原位杂交，将候选区域缩小至仅250 kb。在该区域内，我们鉴定出JAG1——大鼠Jagged1的人类同源物，它编码Notch受体的一种配体。已知细胞间Jagged/Notch相互作用对于早期发育中细胞命运的决定至关重要，这使得它成为人类发育障碍的一个有吸引力的候选基因。确定JAG1完整的外显子 - 内含子结构后，对非缺失AGS患者的DNA样本进行了详细的突变分析，发现了三个移码突变、两个剪接供体突变和一个使改变的等位基因无法表达RNA的突变。我们得出结论，AGS是由JAG1单倍剂量不足引起的。
