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.

肌萎缩性侧索硬化症（ALS）是一种严重的进行性疾病，影响每100,000名个人0.5-3人。这种退化性疾病的特征是皮质，脑干和脊髓中的运动神经元死亡。从临床上讲，这种疾病表现为进行性肌肉无力和萎缩的疾病。典型的疾病是阴险的，总是致命的。神经丝家族由3个基因组成，这些基因编码神经丝（NFL； 8p21），培养基（NFM； 8p21）和重（NFH; NFH; 22q12.2）亚基。运动神经元的周围和近端轴突中的神经丝聚集是ALS病理学的一个特征。虽然这不构成NFS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表达过多会导致类似于这种疾病的病理表型。与加州大学圣地亚哥分校的唐·克利夫兰博士的实验室和马萨诸塞州总医院的罗伯特·布朗博士的实验室合作，我们进行了一个项目，分析了神经丝对ALS的遗传贡献。我们已经在一系列100个家族性ALS病例，100例零星的ALS病例和100个年龄匹配的神经学正常的蛋白酶病例中测序了所有三种神经丝基因的编码区域。我们已经确定了该系列中所有基因中存在的16个新的编码突变，尽管大多数是在编码培养基亚基的基因中。我们通过限制摘要，最初的300个样本以及适用的携带突变的患者家庭成员的原始序列中确认了这些突变。这些数据表明，神经丝基因的变异性在ALS的遗传风险中不起作用。我们还表明，以前认为引起玛丽牙齿疾病2e型charcot的突变（Delta528）实际上是一种罕见的变体，不会引起疾病。