Mutations in ECEL1 Cause Distal Arthrogryposis Type 5D
Mutations in ECEL1 Cause Distal Arthrogryposis Type 5D
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DOI：
10.1016/j.ajhg.2012.11.014
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发表时间：
2013-01-10
影响因子：
9.8
通讯作者：
Bamshad, Michael J.
中科院分区：
文献类型：
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作者：
McMillin, Margaret J.;Below, Jennifer E.;Bamshad, Michael J.
远端关节挛缩症（DA）综合征是最常见的遗传性先天性挛缩症，大约50%的病例是由编码骨骼肌纤维收缩蛋白的基因突变引起的。5D型DA （DASD）是一种罕见的常染色体隐性DA，其特征是先天性手和脚挛缩，并伴有明显的面部特征，包括上睑下垂。我们使用连锁分析和多个近亲家族的全基因组测序来鉴定导致DA5D的内皮素转换酶样1 （ECEL1）突变。对受DA5D影响的7个家族的评估显示，5个家族的ECEL1突变解释了大约70%的病例。ECEL1编码一种神经元内肽酶，在大脑和周围神经中表达。缺乏Ecel1的小鼠表现出运动神经元向骨骼肌终板的末端分支紊乱，导致神经肌肉连接形成不良。我们的研究结果区分了导致先天性挛缩综合征的第二种发育途径。
Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and similar to 50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DASD) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain similar to 70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.