Assessment Of The Neurofilament Genes In ALS

ALS 神经丝基因的评估

• 批准号: 6969744
• 负责人: Andrew B Singleton
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6969744
• 关键词: amyotrophic lateral sclerosis; family genetics; genetic mapping; genetic polymorphism; genetic susceptibility; human genetic material tag; human tissue; molecular pathology; neurofilament; neurogenetics; neuropathology; nucleic acid sequence; patient oriented research; protein structure function

Amyotrophic Lateral Sclerosis (ALS) is a severe progressive condition affecting 0.5-3 persons per 100,000 individuals. This degenerative disease is characterized by motor neuron death in the cortex, brainstem and spinal cord. Clinically the disorder presents as a disease of progressive muscle weakness and atrophy. The typical disease is insidious and invariably fatal. The neurofilament family consists of 3 genes, those encoding neurofilament light (NFL; 8p21), medium (NFM; 8p21) and heavy (NFH; 22q12.2) subunits. Neurofilament aggregation in the perikarya and proximal axons of motor neurons is a characteristic feature of the pathology of ALS. Whilst this does not constitute a causal link between NFs and ALS it is of note that over expression of altered or wild-type neurofilament in mice leads to a pathological phenotype resembling this disease. In collaboration with Dr Don Cleveland's laboratory at the University of California, San Diego and Dr Robert Brown's laboratory at Massachusets General Hospital we have undertaken a project to analyze the genetic contribution of neurofilament to ALS. We have sequenced the coding region of all three neurofilament genes in a series of 100 familial ALS cases, 100 sporadic ALS cases and 100 age matched neurologically normal conrol cases. We have identified 16 novel coding mutations in this series, present in all genes, although the majority are in the gene encoding the medium subunit. We confirmed these mutations by restriction digest, in the original series of 300 samples and, where applicable, in family members of patients carrying mutations. These data suggest that variability in the neurofilament genes does not play a major role in the genetic risk for ALS. We have also shown that a mutation (delta528) previously thought to cause Charcot Marie Tooth Disease type 2E is actually a rare variant which does not cause disease.

肌萎缩性脊髓侧索硬化症 (ALS) 是一种严重的进行性疾病，每 10 万人中有 0.5-3 人受到影响。这种退行性疾病的特征是皮质、脑干和脊髓中的运动神经元死亡。临床上，该疾病表现为进行性肌肉无力和萎缩的疾病。这种典型的疾病是阴险的并且总是致命的。神经丝家族由 3 个基因组成，编码神经丝轻（NFL；8p21）、中（NFM；8p21）和重（NFH；22q12.2）亚基。运动神经元核周和近端轴突中的神经丝聚集是 ALS 病理学的特征。虽然这并不构成 NF 和 ALS 之间的因果关系，但值得注意的是，小鼠中改变或野生型神经丝的过度表达会导致类似于这种疾病的病理表型。我们与加州大学圣地亚哥分校唐·克利夫兰博士的实验室和马萨诸塞州总医院罗伯特·布朗博士的实验室合作开展了一个项目，分析神经丝对 ALS 的遗传贡献。我们对一系列 100 例家族性 ALS 病例、100 例散发性 ALS 病例和 100 例年龄匹配的神经系统正常对照病例中所有三种神经丝基因的编码区进行了测序。我们在该系列中鉴定出了 16 个新的编码突变，它们存在于所有基因中，尽管大多数突变位于编码中等亚基的基因中。我们通过限制性消化在最初的 300 个样本系列中以及在适用的情况下在携带突变的患者的家庭成员中确认了这些突变。这些数据表明，神经丝基因的变异性在 ALS 遗传风险中并不起主要作用。我们还表明，之前被认为会导致 2E 型夏科玛丽牙病的突变 (delta528) 实际上是一种不会引起疾病的罕见突变。