Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia
Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia
复制标题
DOI：
10.1093/hmg/ddv171
复制
发表时间：
2015-08-15
影响因子：
3.5
通讯作者：
Hildebrand, Michael S.
中科院分区：
文献类型：
--
作者：
Damiano, John A.;Afawi, Zaid;Hildebrand, Michael S.
我们研究了一个近亲巴勒斯坦阿拉伯家庭，该家庭分离出常染色体隐性遗传进行性肌阵挛癫痫（PME）并伴有早期共济失调。 PME 是一种罕见且通常致命的综合征，最初对抗癫痫药物有反应，随着时间的推移变得难治，并可能与认知能力下降有关。进行连锁分析，疾病位点缩小至染色体19p13.3。通过传统桑格测序筛选了 14 个候选基因，其中一个基因 LMNB2 是一种新的纯合错义突变，与家族中的 PME 分离。全外显子组测序排除了连锁区间中其他可能的致病性编码变异。 p.His157Tyr 突变位于核纤层蛋白 B2 蛋白 α 螺旋杆的进化上高度保守的区域。突变核纤层蛋白 B2 蛋白的体外组装分析揭示了通常由野生型核纤层蛋白 B2 形成的高度有序的纤维阵列组装中的明显缺陷。我们的数据表明，神经元核层组织的破坏（可能是通过异常神经元迁移）导致癫痫和早期共济失调综合征，并将 PME 的病因扩展到包括核层蛋白功能障碍。
We studied a consanguineous Palestinian Arab family segregating an autosomal recessive progressive myoclonus epilepsy (PME) with early ataxia. PME is a rare, often fatal syndrome, initially responsive to antiepileptic drugs which over time becomes refractory and can be associated with cognitive decline. Linkage analysis was performed and the disease locus narrowed to chromosome 19p13.3. Fourteen candidate genes were screened by conventional Sanger sequencing and in one, LMNB2, a novel homozygous missense mutation was identified that segregated with the PME in the family. Whole exome sequencing excluded other likely pathogenic coding variants in the linked interval. The p.His157Tyr mutation is located in an evolutionarily highly conserved region of the alpha-helical rod of the lamin B2 protein. In vitro assembly analysis of mutant lamin B2 protein revealed a distinct defect in the assembly of the highly ordered fibrous arrays typically formed by wild-type lamin B2. Our data suggests that disruption of the organisation of the nuclear lamina in neurons, perhaps through abnormal neuronal migration, causes the epilepsy and early ataxia syndrome and extends the aetiology of PMEs to include dysfunction in nuclear lamin proteins.