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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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计划的重点是鉴定和表征与遗传运动和神经肌肉疾病有关的基因和遗传机制。肌原纤维肌病：我们以前已将Desmin基因（DES）确定为心脏和骨骼肌病的原因。迄今为止，该基因中的52个突变已被证明是致病性的。在该实验室进行的新研究表明，脱敏基因的突变导致147例明确诊断为肌原纤维肌病的患者中有62％的疾病。其余的38％现在与其他四个基因的突变有关，Myot为28％，ZASP为3％，Cryab和Flnc分别为1％，而5％的患者患有多个基因突变。我们的分析建立了这些遗传亚型之间足够的临床，电生理和肌病学相似性，从而使它们可以将其分类为肌原纤维肌病。同时，我们发现了在诊断和亚型特异性治疗和管理中应考虑的遗传多样的亚型之间的实质性表型区别。 Nemaline肌病：我们在四个血统中重新分析了NEM6候选区域，并确定病因基因位于15q22.31染色体上的6.7兆巴区域。筛选该区域中多个基因的筛选导致鉴定出一个未知的KBTBD13基因，该基因包含一个外显子编码458个氨基酸的KBTBD13蛋白和49 kDa的KBTBD13蛋白，在骨骼和心脏肌肉中表达了49 kDa。蛋白质结构分析允许将KBTBD13分类为BTB/Kelch超家族的成员。 KBTBD13在骨骼肌中的功能作用和氯肾肌病的发病机理是进一步研究的主题。引起基本震颤的基因的染色体图：以前，我们在两个美国家庭中报道了一个新的有希望的染色体基因座，并在其他三个家庭中将疾病基因映射到了11p15染色体的另一个基因座。现在，我们重新评估了一个当地的大家庭，该家庭没有使用较新的生理学和基因分型技术来表现与这些基因座的任何一个联系。我们现在正在使用外显子组测序进行候选基因检测。研究正在进行中。 Vilyuisk脑脊髓炎：我们使用大量具有临床和病理诊断的患者分析了西伯利亚东部西伯利亚viliuisk脑脊髓炎流行的年度发病率和其他特征。流行高度的平均年发病率达到每100,000人口8.8，主要影响了年轻人。最初的爆发发生在Viliui中期，后来蔓延到邻近地区，最终蔓延到人口稠密的西南地区和首都雅库茨克附近的中央地区内的遥远地区，当地人口中发生了许多新案件。结果表明，从地方性村庄迁移的人类迁徙加剧导致这种疾病在新社区的出现。最近的社会和人口变化大概导致疾病发病率下降。