Genotype-Phenotype Correlations in Movement and Neuromuscular Disorders

运动和神经肌肉疾病的基因型-表型相关性

• 批准号: 6432938
• 负责人: Lev G Goldfarb
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 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/6432938
• 关键词: amyotrophic lateral sclerosis; cerebellar ataxia /dyskinesia; clinical research; family genetics; fibrous protein; gene mutation; genetic screening; genetic susceptibility; human subject; muscle disorders; neurogenetics; neuromuscular disorder; spongiform encephalopathy; superoxide dismutase

The Clinical Neurogenetics Unit research program is focused on identification and characterization of genes and genetic mechanisms involved in hereditary a) movement disorders, b) neuromuscular disorders, and c) prion diseases. Major findings: A clinically and pathologically distinct type of cardioskeletal myopathy is associated with mutations in the desmin gene: eight novel causative mutations have now been identified and described, and each mutation tested in a cell culture expression system. Digenic inheritance of malignant hyperthermia was established in a large American family with a novel mutation identified in the RYR1 gene on chromosome 19 and a significant linkage to a locus on chromosome 7q. An unusual phenotype with myoclonus, seizures and unique distribution of prion protein plaques in the cortex is associated with a novel H187R mutation in the prion protein (PRNP) gene. World distribution of hereditary prion encephalopathy caused by the PRNP E200K mutation indicate that both founder effect and new mutations determine the current geographic distribution. Genetically predetermined susceptibility to kuru is tightly linked to a M/V polymorphism in the PRNP gene. A novel mutation in exon 3B of the proteolipid protein (PLP) gene was identified as the cause of a late-onset spastic paraplegia with variable expression in heterozygotes.

临床神经遗传学单位研究计划的重点是识别和表征基因和遗传机制涉及遗传性a）运动障碍，B）神经肌肉疾病，和c）朊病毒疾病。主要发现：一种临床和病理上不同类型的心脏骨骼肌病与结蛋白基因突变相关：现已鉴定和描述了8种新的致病突变，并在细胞培养表达系统中测试了每种突变。恶性高热的双基因遗传是在一个美国大家庭中建立的，该大家庭在19号染色体上的RYR 1基因中发现了一种新的突变，并与染色体7 q上的一个位点有显著的连锁关系。肌阵挛、癫痫发作和朊蛋白斑块在皮质中的独特分布的不寻常表型与朊蛋白（PRNP）基因中的新型H187 R突变相关。由PRNP E200 K突变引起的遗传性朊病毒脑病的世界分布表明，创始人效应和新的突变决定了目前的地理分布。基因决定的库鲁病易感性与PRNP基因的M/V多态性紧密相关。蛋白脂质蛋白（PLP）基因外显子3B的一种新突变被确定为晚发性痉挛性截瘫的原因，在杂合子中具有可变的表达。