Genotype-phenotype Correlations In Movement And Neuromus

运动和神经肌肉的基因型-表型相关性

• 批准号: 6675683
• 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/6675683
• 关键词: calcium channel; cerebellar ataxia /dyskinesia; clinical research; degenerative motor system disease; family genetics; fibrous protein; gene mutation; genetic polymorphism; genetic screening; genetic susceptibility; genotype; hereditary peripheral nervous system disorder; human subject; human tissue; interview; malignant hyperthermia; neurogenetics; neuromuscular disorder; paraplegia; phenotype; questionnaires; scrapie; spastic paralysis; spongiform encephalopathy; tissue /cell culture

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: sixteen causative mutations have now been identified and described, and adverse effects of each mutation tested in a cell culture expression system. An extremely aggressive variant of malignant hyperthermia was characterized in large North and South American families and linked to a novel mutation in the ryanodine receptor (RYR1) gene. A new study shows that worldwide distribution of hereditary Creutzfeldt-Jakob disease/Fatal Insomnia associated with the PRNP D178N mutation depends on recurrent mutations rather than founder effect. Genetic susceptibility to kuru and new variant Creutzfeldt-Jakob disease is tightly linked to a M/V polymorphism in the PRNP gene, providing a model for predictions of the length and size of the developing epidemic of variant CJD associated with mad cow disease. Tremor-dystonia type of essential tremor in a large American family is shown to be linked to a 7cM locus on chromosome 6p. Evidence is presented that a herpesvirus caused a large epidemic of Viliuisk encephalomyelitis in a limited area of Eastern Siberia.

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：目前已确定和描述了16种致病突变，并在细胞培养表达系统中测试了每种突变的不良影响。在北美和南美的大家族中发现了一种极具侵袭性的恶性高热变体，其特征与ryanodine受体（RYR1）基因的一种新突变有关。一项新的研究表明，与PRNP D178N突变相关的遗传性克雅氏病/致死性失眠症的全球分布取决于复发性突变，而不是奠基者效应。库鲁病和新型克雅氏病的遗传易感性与PRNP基因的M/V多态性密切相关，这为预测与疯牛病相关的变异型克雅氏病流行的长度和大小提供了一个模型。震颤-肌张力障碍型特发性震颤在一个美国大家族中被证明与6p染色体上7cM位点有关。有证据表明，一种疱疹病毒在东西伯利亚的一个有限地区引起了维利乌斯克脑脊髓炎的大规模流行。