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: 8557020
• 负责人: Lev G Goldfarb
• 金额: $ 33.9万
• 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/8557020
• 关键词: 11p15; 6p23; Affect; Amendment; American; Amino Acids; Amish; Area; Candidate Disease Gene; Capital; Cardiac; Characteristics; Charcot-Marie-Tooth Disease; Chromosome Mapping; Chromosomes; Cities; Clinical; Clinical Protocols; Collaborations; Communities; Data Set; Defect; Desmin; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Outbreaks; Distant; Encephalomyelitis; Epidemic; Essential Tremor; Evaluation; Exons; Family; Genes; Genetic; Genetic screening method; Genotype; Goals; Height; Incidence; Inherited; Laboratories; Maps; Molecular; Movement Disorders; Mutation; Mutation Detection; Myocardium; Myopathy; National Institute of Neurological Disorders and Stroke; Nemaline Myopathies; Neurodegenerative Disorders; Neuromuscular Diseases; Neurosciences; Pathogenesis; Pathogenicity; Patients; Phenotype; Physiology; Population; Proteins; Reporting; Research; Role; Screening procedure; Services; Siberia; Skeletal Muscle; Techniques; Therapeutic Intervention; Time; exome; genetic analysis; genetic pedigree; human migration; improved; member; molecular mass; neurogenetics; physical mapping; programs; protein structure; skeletal; social; young adult

The Clinical Neurogenetics research program is focused on identification and characterization of genes and genetic mechanisms involved in hereditary movement and neuromuscular disorders. MYOFIBRILLAR MYOPATHIES: We have previously identified desmin gene (DES) as the cause of cardiac and skeletal myopathy. To-date, 52 mutations in this gene have proven to be pathogenic. New studies conducted in this laboratory have shown that mutations in desmin gene caused the disease in 62% of 147 patients with a definite diagnosis of myofibrillar myopathy. The remaining 38% have now been associated with mutations in four other genes, MYOT in 28%, ZASP in 3%, CRYAB and FLNC in 1% each, and 5% of patients had mutations in more than one gene. Our analysis established sufficient clinical, electrophysiological and myopathological similarity between these genetic subtypes allowing to classify them as Myofibrillar myopathies. At the same time, we uncovered substantial phenotypic distinctions between the genetically diverse subtypes that should be considered in diagnostics and subtype-specific treatments and management. NEMALINE MYOPATHY: We reanalyzed the NEM6 candidate region in four pedigrees and determined that the causative gene is located in a 6.7-megabase region on chromosome 15q22.31. Screening of multiple genes in this area resulted in the identification of a previously unknown KBTBD13 gene that contains a single exon encoding a KBTBD13 protein of 458 amino acids and molecular mass of 49 kDa expressed in skeletal and cardiac muscles. Protein structure analysis allowed to classify KBTBD13 as a member of the BTB/Kelch superfamily. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of nemaline myopathy are subjects of further studies. CHROMOSOMAL MAPPING OF GENES CAUSING ESSENTIAL TREMOR: Previously, we reported a new promising chromosomal locus on 6p23 in two American families and mapped the disease gene in three other families to another locus on chromosome 11p15. We have now re-evaluated a large local family that did not show linkage to any of these loci by using newer physiology and genotyping techniques. We are now using exome sequencing for candidate gene detection. The studies are in progress. VILYUISK ENCEPHALOMYELITIS: We analyzed annual incidence rates and other characteristics of the Viliuisk encephalomyelitis epidemic in Eastern Siberia using a large dataset of patients with clinically and pathologically confirmed diagnoses. The average annual incidence rate at the height of the epidemic reached 8.8 per 100,000 population and affected predominantly young adults. The initial outbreak occurred in the mid-Viliui region and later spread to neighboring regions and eventually to distant localities within more densely populated southwestern territories and a central region near the capital city of Yakutsk, with many new cases occurring in the local populations. The results suggest that intensified human migration from endemic villages led to the emergence of this disease in new communities. Recent social and demographic changes have presumably contributed to a decline in disease incidence.

临床神经遗传学研究项目的重点是遗传性运动和神经肌肉疾病所涉及的基因和遗传机制的识别和表征。 肌纤维肌病：我们之前已确定结蛋白基因 (DES) 是心脏和骨骼肌病的病因。迄今为止，该基因的 52 个突变已被证明具有致病性。该实验室进行的新研究表明，在 147 名确诊为肌原纤维肌病的患者中，62% 的患者是由结蛋白基因突变引起的。其余 38% 的患者目前与其他 4 个基因的突变有关，其中 28% 为 MYOT，3% 为 ZASP，3% 为 CRYAB 和 FLNC，5% 的患者有不止一种基因突变。我们的分析确定了这些遗传亚型之间足够的临床、电生理学和肌病理学相似性，从而可以将它们分类为肌原纤维肌病。与此同时，我们发现了遗传多样性亚型之间的显着表型差异，在诊断和亚型特异性治疗和管理中应考虑这些差异。 线形肌病：我们重新分析了四个家系的 NEM6 候选区域，确定致病基因位于染色体 15q22.31 上的 6.7 兆碱基区域。对该区域的多个基因进行筛选，结果鉴定出一种先前未知的 KBTBD13 基因，该基因包含编码 458 个氨基酸、分子量为 49 kDa 的 KBTBD13 蛋白的单个外显子，在骨骼肌和心肌中表达。蛋白质结构分析将 KBTBD13 归类为 BTB/Kelch 超家族的成员。 KBTBD13 在骨骼肌中的功能作用和线状肌病的发病机制是进一步研究的课题。 导致特发性震颤的基因的染色体定位：此前，我们报道了两个美国家庭中 6p23 上的一个新的有希望的染色体位点，并将其他三个家庭中的疾病基因定位到染色体 11p15 上的另一个位点。我们现在使用更新的生理学和基因分型技术重新评估了一个当地的大家族，该家族没有显示出与任何这些基因座的联系。我们现在使用外显子组测序来检测候选基因。研究正在进行中。 VILYUISK 脑脊髓炎：我们使用大量临床和病理确诊患者数据集分析了东西伯利亚 Viliuisk 脑脊髓炎流行的年发病率和其他特征。疫情高峰期的年平均发病率达到每 10 万人 8.8 例，主要影响年轻人。疫情最初发生在维留伊中部地区，后来蔓延到邻近地区，最终蔓延到人口较稠密的西南部地区和首都雅库茨克附近的中部地区，当地居民中出现了许多新病例。结果表明，来自流行村庄的人口迁徙加剧导致了这种疾病在新社区的出现。最近的社会和人口变化可能导致了疾病发病率的下降。