Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de psychiatrie et neurosciences, Université Laval, Ste-Foy, QC, Canada G1V 4G2.
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21777-82. doi: 10.1073/pnas.0902174106. Epub 2009 Dec 9.
Recently, chromogranins were reported to interact specifically with mutant forms of superoxide dismutase that are linked to amyotrophic lateral sclerosis (ALS). This interaction led us to analyze the frequencies of sequence variants of the CHGB gene in ALS patients and matched controls from three different countries. Of particular interest was the finding of the P413L CHGB variant present in 10% of ALS patients (n = 705) as compared to 4.5% in controls (n = 751), conferring a 2.2-fold greater relative risk to develop the disease (P < 0.0001). This effect was mainly contributed by the samples of French origin that yielded a frequency of the P413L variation at 17% in ALS (n = 289) and 5% in controls (n = 448), conferring a 3.3-fold greater risk to develop ALS. Furthermore, the P413L CHGB variant is associated with an earlier age of onset by almost a decade in both sporadic ALS and familial ALS cases. Genetic variation influencing age of onset in ALS had not previously been reported. Expression of fusion CHGB-EGFP constructs in SHSY-5Y cells revealed that the P413L variation can cause defective sorting of CHGB into secretory granules. The finding that CHGB may act as a susceptibility gene and modifier of onset in ALS is consistent with the emerging view that dysfunction of the secretory pathway may contribute to increased vulnerability of motor neurons.
最近，有报道称嗜铬粒蛋白与与肌萎缩侧索硬化症（ALS）相关的超氧化物歧化酶的突变体形式特异性相互作用。这一相互作用促使我们分析了三个不同国家的 ALS 患者和匹配对照人群中 CHGB 基因序列变异的频率。特别有趣的是，我们发现 P413L CHGB 变体在 10%的 ALS 患者（n = 705）中存在，而在对照组（n = 751）中仅为 4.5%，这使疾病发展的相对风险增加了 2.2 倍（P < 0.0001）。这种效应主要归因于来自法国的样本，其中 P413L 变异在 ALS 患者中的频率为 17%（n = 289），在对照组中为 5%（n = 448），这使疾病发展的风险增加了 3.3 倍。此外，P413L CHGB 变体与散发性 ALS 和家族性 ALS 病例的发病年龄提前近十年相关。以前没有报道过影响 ALS 发病年龄的遗传变异。在 SHSY-5Y 细胞中表达融合的 CHGB-EGFP 构建体表明，P413L 变异可导致 CHGB 错误地分拣到分泌颗粒中。CHGB 可能作为 ALS 的易感基因和发病修饰因子的发现与不断出现的观点一致，即分泌途径的功能障碍可能导致运动神经元易感性增加。
