A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis
A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis
复制标题
DOI：
10.1086/425287
复制
发表时间：
2004-11-01
影响因子：
9.8
通讯作者：
Zatz, M
中科院分区：
文献类型：
--
作者：
Nishimura, AL;Mitne-Neto, M;Zatz, M
运动神经元疾病(MND)是一组累及上、下运动神经元的神经退行性疾病，如肌萎缩侧索硬化症(ALS)、脊髓性肌萎缩症(SMA)、进行性球麻痹和原发性侧索硬化症。最近，我们在一个巴西白人大家庭中定位了一个位于20q13.3的非典型ALS/MND(非典型肌萎缩侧索硬化症[ALS8])的新基因座。在这里，我们报告了在该家族的患者中发现了一个新的囊泡相关膜蛋白/突触素相关膜蛋白B(VAPB)基因的错义突变。随后，在另外6个家系的患者中发现了相同的突变，但临床病程不同，如ALS8、晚发型SMA和典型的进展迅速的严重ALS。尽管不可能将所有这些家族联系在一起，但单倍型分析表明存在创始人效应。囊泡相关蛋白是细胞内膜蛋白，可与微管结合，并已被证明在膜运输中具有功能。这些数据表明，临床上可变的MND可能是由细胞内膜转运功能障碍引起的。
Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND ( atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking.