Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1
Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1
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DOI：
10.1186/s13023-014-0174-9
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发表时间：
2014-11-26
影响因子：
3.7
通讯作者：
Servais, Laurent
中科院分区：
文献类型：
--
作者：
Dorboz, Imen;Coutelier, Marie;Servais, Laurent
背景资料：肌张力障碍、小脑萎缩和心肌病构成了一种罕见的关联。方法：我们使用纯合性作图和全外显子测序来确定突变，在培养的成纤维细胞上进行蛋白质印迹和免疫标记来证明蛋白质的低表达和错误定位。我们报告一个男孩出生于近亲健康的父母，谁提出了在3岁的快速进展性肌张力障碍，进行性小脑萎缩和扩张型心肌病我们确定了纯合性区域，并进行了全外显子组测序，揭示了TOR 1AIP 1的纯合错义突变。该突变在对照中不存在，导致高度保守的谷氨酸变为丙氨酸。TOR 1AIP 1编码核纤层相关多肽1（LAP 1），一种在内核膜中广泛表达的跨膜蛋白。LAP 1与在DYT 1-肌张力障碍中突变的蛋白质torsinA相互作用。在患者的成纤维细胞中的体外研究揭示了LAP 1的表达减少及其在内质网中的错误定位和聚集作为潜在的致病机制。TOR 1 AIP 1突变的致病作用得到以下方面的支持：a）涉及高度保守的氨基酸，B）对照中不存在突变，c）LAP 1与扭转蛋白A的功能性相互作用，和d）LAP 1在患者细胞中的错误定位。值得注意的是，在LAP 1缺失小鼠和TOR 1AIP 1无义突变患者中报告了心肌病。其他病例将有助于描述LAP 1相关突变的临床谱。
Background: Dystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association.Methods: We used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and immunolabelling on cultured fibroblasts to demonstrate the lower expression and the mislocalization of the protein.Results: We report on a boy born from consanguineous healthy parents, who presented at three years of age with rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy. We identified regions of homozygosity and performed whole exome sequencing that revealed a homozygous missense mutation in TOR1AIP1. The mutation, absent in controls, results in a change of a highly conserved glutamic acid to alanine. TOR1AIP1 encodes lamina-associated polypeptide 1 (LAP1), a transmembrane protein ubiquitously expressed in the inner nuclear membrane. LAP1 interacts with torsinA, the protein mutated in DYT1-dystonia. In vitro studies in fibroblasts of the patient revealed reduced expression of LAP1 and its mislocalization and aggregation in the endoplasmic reticulum as underlying pathogenic mechanisms.Conclusions and relevance: The pathogenic role of TOR1AIP1 mutation is supported by a) the involvement of a highly conserved amino acid, b) the absence of the mutation in controls, c) the functional interaction of LAP1 with torsinA, and d) mislocalization of LAP1 in patient cells. Of note, cardiomyopathy has been reported in LAP1-null mice and in patients with the TOR1AIP1 nonsense mutation. Other cases will help delineate the clinical spectrum of LAP1-related mutations.