Genotype-Phenotype Correlations in Movement and Neuromuscular Disorders

临床神经遗传学单位研究项目的重点是识别和表征遗传基因和遗传机制涉及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骨骼肌病与desmin基因突变有关：现在已经确定和描述了八种新的致病突变，每种突变都在细胞培养表达系统中进行了测试。在美国一个大家族中发现了恶性高热的基因遗传，该家族在19号染色体上的RYR1基因上发现了一个新的突变，并与染色体7q上的一个位点有显著的连锁关系。一种不寻常的表型，包括肌阵挛、癫痫和皮层中朊蛋白斑块的独特分布，与朊蛋白（PRNP）基因的新型H187R突变有关。由PRNP E200K突变引起的遗传性朊病毒脑病的世界分布表明，创始人效应和新突变共同决定了当前的地理分布。遗传上预先确定的库鲁病易感性与PRNP基因的M/V多态性密切相关。蛋白脂蛋白（PLP）基因外显子3B的一个新突变被确定为迟发性痉挛性截瘫的原因，在杂合子中表达可变。

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.