Mutation in MPDZ causes severe congenital hydrocephalus
Mutation in MPDZ causes severe congenital hydrocephalus
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DOI：
10.1136/jmedgenet-2012-101294
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发表时间：
2013-01-01
影响因子：
4
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
--
作者：
Al-Dosari, Mohammed S.;Al-Owain, Mohammed;Alkuraya, Fowzan S.
背景先天性脑积水是一种重要的出生缺陷，其病因和临床表现具有多样性。虽然遗传学被认为在非综合征性先天性脑积水的病因学中起着重要作用，但绝大多数病例缺乏L1 CAM突变，这是迄今为止唯一确定的疾病基因。本研究的目的是确定一个新的遗传原因的先天性hydrocephalus.Methods先天性脑积水家系的临床表型，并在一个家庭，autozogisty定位和连锁分析。在候选位点内的基因测序，其次是有针对性的测序可能的候选基因在其他两个family.Results我们已经确定了一个家庭中，严重的先天性脑积水的通信类型如下常染色体隐性遗传模式。连锁分析和同源性定位缩小了临界区间为6.9 Mb的9p24.1-p22.3跨越只有6个基因。这些基因的直接测序揭示了MPDZ的截短突变，编码紧密连接蛋白。值得注意的是，我们还确定了相同的创始人突变死产与巨大的先天性脑积水从另一个family.Conclusions我们的数据强烈支持候选人的MPDZ作为一种新的先天性脑积水疾病基因。
Background Congenital hydrocephalus is an important birth defect that is heterogeneous in aetiology and clinical presentation. Although genetics is believed to play an important role in the aetiology of non-syndromic congenital hydrocephalus, the overwhelming majority of cases lack mutations in L1CAM, the only disease gene identified to date. The purpose of this study is to identify a novel genetic cause of congenital hydrocephalus.Methods Families with congenital hydrocephalus were phenotyped clinically and, in one family, autoyzogisty mapping and linkage analysis were pursued. Sequencing of the genes within the candidate locus was followed by targeted sequencing of the likely candidate gene in two other families.Results We have identified a family in which severe congenital hydrocephalus of the communicating type follows an autosomal recessive mode of inheritance. Linkage analysis and autozygosity mapping narrowed the critical interval to 6.9 Mb on 9p24.1-p22.3 spanning just six genes. Direct sequencing of these genes revealed a truncating mutation in MPDZ, encoding a tight junction protein. Remarkably, we have also identified the same founder mutation in a stillbirth with massive congenital hydrocephalus from another family.Conclusions Our data strongly support the candidacy of MPDZ as a novel congenital hydrocephalus disease gene.