Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière INSERM UMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France.
J Med Genet. 2010 Aug;47(8):554-60. doi: 10.1136/jmg.2010.077180. Epub 2010 Jun 24.
Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS).
The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations.
31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration.
This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
SOD1、ANG、VAPB、TARDBP 和 FUS 基因突变已在肌萎缩侧索硬化症（ALS）中被发现。
通过系统筛选在法国招募的 162 个家族和 500 个对照者（1000 条染色体）的队列，使用分子分析技术并进行表型-基因型相关性分析，来估计不同突变对 ALS 的相对贡献。
在 36 名患者（20 名 SOD1、1 名 ANG、1 名 VAPB、7 名 TARDBP 和 7 名 FUS）中发现了 31 个致病性错义突变。令人惊讶的是，两名 FUS 突变携带者也携带 ANG 变异体。发现了一个具有 P56S VAPB 突变的日本家族。发现了七个新突变（三个在 SOD1 中，两个在 TARDBP 中，两个在 FUS 中）。它们都未在对照者中被检测到。在包括五个携带新突变的家系在内的 11 个家系中，检测到的突变与疾病的分离得到了确认。对 SOD1、TARDBP、FUS 和其他家族性 ALS 患者（在筛选基因中没有突变）的临床比较显示，发病部位（SOD1 主要为下肢，TARDBP 突变主要为上肢）、发病年龄（FUS 突变较年轻）和寿命（FUS 携带者较短）存在差异。三分之一的 SOD1 患者存活超过 7 年：这些患者的疾病发作比那些具有更典型病程的患者更早。在 FUS 突变中也观察到差异，R521H FUS 突变与疾病持续时间较长有关。
本研究确定了与 ALS 相关的新遗传关联，并提供了与以前报道的和新的突变相关的表型-基因型相关性。
