Evidence for an oligogenic basis of amyotrophic lateral sclerosis
Evidence for an oligogenic basis of amyotrophic lateral sclerosis
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DOI：
10.1093/hmg/dds199
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发表时间：
2012-09-01
影响因子：
3.5
通讯作者：
van den Berg, Leonard H.
中科院分区：
文献类型：
--
作者：
van Blitterswijk, Marka;van Es, Michael A.;van den Berg, Leonard H.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，具有显着的遗传成分。在受其家族形式影响的谱系中，经常观察到不完全外显率。我们假设这可能是由多个基因中风险变异的复杂遗传引起的。因此，我们对来自 97 个家庭的 111 名家族性 ALS (FALS) 患者以及大量散发性 ALS (SALS) 患者和对照受试者进行了 TAR DNA 结合蛋白 (TARDBP)、肉瘤融合/脂肪肉瘤翻译 (FUS/TLS)、超氧化物歧化酶-1 (SOD1)、血管生成素 (ANG) 和 9 号染色体开放阅读框 72 突变的筛查 （C9orf72）。在 48 个 FALS 家族、8 个 SALS 患者和 0.5 个对照受试者中发现了突变。在五个 FALS 家族中，我们发现了 ALS 相关基因的多个突变。我们检测到 FUS/TLS 和 TARDBP 突变与 ANG 突变相结合，以及 C9orf72 重复扩增与 TARDBP、SOD1 和 FUS/TLS 突变的结合。统计分析表明，FALS 中多种突变的存在超出了偶然的预期 (P 1.57 10(7))。寡基因基础最令人信服的证据是在 TARDBP 中具有 p.N352S 突变的个体中发现的，该突变在 5 个 FALS 家族和 3 名明显的 SALS 患者中检测到。谱系学和单倍型分析表明，这些个体拥有共同的祖先。我们获得了 14 名具有这种 TARDBP 突变的患者的 DNA，其中 50 名患者有额外的突变（ANG、C9orf72 或纯合 TARDBP）。在此，我们为 ALS 的寡基因病因学提供了证据。这可能对解释整个外显子组/基因组实验（旨在识别新的 ALS 相关基因）和遗传咨询（尤其是未受影响的家庭成员）具有重要意义。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a substantial heritable component. In pedigrees affected by its familial form, incomplete penetrance is often observed. We hypothesized that this could be caused by a complex inheritance of risk variants in multiple genes. Therefore, we screened 111 familial ALS (FALS) patients from 97 families, and large cohorts of sporadic ALS (SALS) patients and control subjects for mutations in TAR DNA-binding protein (TARDBP), fused in sarcoma/translated in liposarcoma (FUS/TLS), superoxide dismutase-1 (SOD1), angiogenin (ANG) and chromosome 9 open reading frame 72 (C9orf72). Mutations were identified in 48 of FALS families, 8 of SALS patients and 0.5 of control subjects. In five of the FALS families, we identified multiple mutations in ALS-associated genes. We detected FUS/TLS and TARDBP mutations in combination with ANG mutations, and C9orf72 repeat expansions with TARDBP, SOD1 and FUS/TLS mutations. Statistical analysis demonstrated that the presence of multiple mutations in FALS is in excess of what is to be expected by chance (P 1.57 10(7)). The most compelling evidence for an oligogenic basis was found in individuals with a p.N352S mutation in TARDBP, detected in five FALS families and three apparently SALS patients. Genealogical and haplotype analyses revealed that these individuals shared a common ancestor. We obtained DNA of 14 patients with this TARDBP mutation, 50 of whom had an additional mutation (ANG, C9orf72 or homozygous TARDBP). Hereby, we provide evidence for an oligogenic aetiology of ALS. This may have important implications for the interpretation of whole exome/genome experiments designed to identify new ALS-associated genes and for genetic counselling, especially of unaffected family members.