DHPLC Mutation Analysis of Jagged1 (JAG1) Reveals Six Novel Mutations in Australian Alagille Syndrome Patients
DHPLC Mutation Analysis of Jagged1 (JAG1) Reveals Six Novel Mutations in Australian Alagille Syndrome Patients
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DOI：
10.1002/humu.9095
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发表时间：
2002-12-01
期刊：
影响因子：
3.9
通讯作者：
Anderson, Gregory J.
中科院分区：
文献类型：
--
作者：
Heritage, Mandy L.;MacMillan, John C.;Anderson, Gregory J.
Alagille综合征(AGS)是一种常染色体显性遗传性疾病，以肝脏、心脏、骨骼、眼睛和面部发育异常为特征。Jagged1基因的突变已被发现导致AGS表型。应用变性高效液相色谱(DHPLC)突变分析方法，对来自14个家系的20名AGS患者进行了Jagged1基因突变的筛查。在14个先证者和受影响的家庭成员中发现了11个不同的Jagged1突变，其中6个是新的。突变包括4个小缺失(36.6%)、1个小插入(9.1%)、3个错义突变(27.3%)、1个无义突变(9.1%)和2个剪接供区突变(18.2%)。这两个新发现的剪接点突变导致Jagged1mRNA的异常剪接，导致JAG1过早截断。我们课题组先前发现的内含子13的剪接受体位点突变也导致了Jagged1mRNA的多重剪接异常，从而消除了外显子14和15。这一研究结果与野生型JAG1的单倍体不足和/或突变的JAG1产生的显性负效应导致AGS表型的说法是一致的。(C)2002年Wiley-Liss，Inc.
Alagille syndrome (AGS) is an autosomal dominant disorder characterized by abnormal development of the liver, heart, skeleton, eye, and face. Mutations in the Jagged1 gene have been found to result in the AGS phenotype. Using denaturing high performance liquid chromatography (DHPLC) mutation analysis we have screened 20 individuals with symptoms of AGS from 14 families for mutations within Jagged1. Eleven distinct Jagged1 mutations, six of which are novel, were identified in the 14 probands and affected family members. The mutations include four small deletions (36.6%), one small insertion (9.1%), three missense mutations (27.3%), one nonsense mutation (9.1%) and two splice donor site mutations (18.2%). The two newly identified splice site mutations were shown to cause the aberrant splicing of Jagged1 mRNA resulting in premature truncation of JAG1. A splice acceptor site mutation previously identified by our group in intron 13 was also shown to cause multiple splicing abnormalities of Jagged1 mRNA, consequently removing exons 14 and 15. The results of this study are consistent with the proposal that either haploinsufficiency for wild-type JAG1 and/or dominant negative effects produced by mutated JAG1 are responsible for the AGS phenotype. (C) 2002 Wiley-Liss, Inc.