Genotype-Phenotype Correlations in Movement and Neuromuscular Disorders

临床神经遗传学单位的研究计划集中于与遗传性a)运动障碍、b)神经肌肉障碍和c)Pron疾病相关的基因和遗传机制的识别和表征。主要发现：一种临床和病理上不同的心脏骨骼肌病类型与结蛋白基因突变有关：目前已发现并描述了八种新的致病突变，每一种突变都在细胞培养表达系统中进行了测试。恶性高热症的数字遗传是在一个美国大家庭中建立的，在19号染色体上的RYR1基因中发现了一个新的突变，并与7q号染色体上的一个基因座有显著的连锁。一种罕见的表型肌阵挛、癫痫发作和皮质区独特的普恩蛋白斑块分布与普恩蛋白(PRNP)基因的H187R突变有关。由PRNP E200K突变引起的遗传性Prion脑病的全球分布表明，方正效应和新突变共同决定了当前的地理分布。库鲁病的遗传易感性与PRNP基因的M/V多态密切相关。蛋白脂蛋白(PLP)基因外显子3B上的一个新突变被确认为在杂合子中表达可变的晚发性痉挛截瘫的原因。

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.