Kwok Chun Tak, Wang Hsiang-Ya, Morris Alex G, Smith Bradley, Shaw Christopher, de Belleroche Jackie
Neurogenetics Group, Division of Brain Sciences, Faculty of Medicine, Imperial College London, UK.
Centre for Neurodegeneration Research, Department of Clinical Neurosciences, Institute of Psychiatry, King's College London, SE5 8AF, UK.
J Neurol Sci. 2015 Feb 15;349(1-2):209-13. doi: 10.1016/j.jns.2015.01.021. Epub 2015 Jan 17.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing loss of motor neurons in the spinal cord, brain stem and cerebral cortex. Mutations in the Valosin containing protein (VCP) gene have recently been identified in Familial ALS (FALS) patients, accounting for ~1% of all FALS cases. In order to study the frequency of VCP mutations in UK FALS patients, we have screened the exons known to harbour mutations together with 3' and 5' UTR sequences. No coding changes were identified in this UK cohort and no common polymorphisms were associated with FALS. However, we identified an imperfect hexanucleotide expansion (8 repeats), c.-221_-220insCTGCCACTGCCACTGCCG, in the 5'UTR of a FALS case and a 7-repeat hexanucleotide repeat in a Sporadic ALS case (SALS) that were not present in 219 UK controls. Subsequent screening of sequence data from 1844 controls (1000 genomes Phase 3) revealed the presence of the 7-repeat (0.3%) and a single individual with an 8-repeat containing a homogeneous insert [CTGCCG]3 but no individuals with the heterogeneous insert found in FALS ([CTGCCA]2[CTGCCG]). Two novel single base pair substitutions, c.-360G>C and c.2421+94C>T, were found in FALS cases in the 5' and 3' UTRs respectively. The hexanucleotide expansion and c.-360G>C were predicted to be pathogenic and were found in FALS cases harbouring C9orf72 expansions. The SALS case with a 7 repeat lacked a C9orf72 expansion. We conclude that VCP mutations are not a major cause of FALS in the UK population although novel rare variations in the 5' UTR of the VCP gene may be pathogenic.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，会导致脊髓、脑干和大脑皮层中的运动神经元丧失。最近在家族性ALS（FALS）患者中发现了含缬酪肽蛋白（VCP）基因的突变，约占所有FALS病例的1%。为了研究英国FALS患者中VCP突变的频率，我们筛选了已知含有突变的外显子以及3'和5'非翻译区（UTR）序列。在这个英国队列中未发现编码变化，也没有常见的多态性与FALS相关。然而，我们在一例FALS病例的5'UTR中鉴定出一个不完全六核苷酸扩增（8次重复），即c.-221_-220insCTGCCACTGCCACTGCCG，以及一例散发性ALS病例（SALS）中的7次重复六核苷酸重复，而在219名英国对照中未发现这些情况。随后对来自1844名对照（1000基因组计划第3阶段）的序列数据进行筛选，发现了7次重复（0.3%）以及一名个体具有包含[CTGCCG]3的均匀插入的8次重复，但没有发现具有FALS中发现的异质插入（[CTGCCA]2[CTGCCG]）的个体。在FALS病例的5'和3'UTR中分别发现了两个新的单碱基对替换，即c.-360G>C和c.2421+94C>T。六核苷酸扩增和c.-360G>C被预测具有致病性，并且在携带C9orf72扩增的FALS病例中发现。具有7次重复的SALS病例没有C9orf72扩增。我们得出结论，尽管VCP基因5'UTR中的新的罕见变异可能具有致病性，但VCP突变不是英国人群中FALS的主要原因。
