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: 8342219
• 负责人: Lev G Goldfarb
• 金额: $ 79.71万
• 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/8342219
• 关键词: 11p15; 6p23; Adolescent; 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; Distal; Distant; Encephalomyelitis; Epidemic; Essential Tremor; Etiology; Evaluation; Exons; Family; Gene Mutation; Genes; Genetic; Genetic screening method; Genotype; Glycine-tRNA Ligase; Goals; Height; Incidence; Inherited; Laboratories; Maps; Molecular; Motor; Movement Disorders; Muscular Atrophy; 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; Spinal Muscular Atrophy; Techniques; Testing; Therapeutic Intervention; Time; Upper Extremity; axonopathy; cohort; 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. CHARCOT-MARIE-TOOTH DISEASE TYPE 2D AND SPINAL MUSCULAR ATROPHY TYPE V: We have previously identified glycyl-tRNA synthetase (GARS) gene mutations as the cause of autosomal dominant motor distal neuronopathy/axonopathy. We now tested a group of sporadic patients with a presumptive diagnosis of CMT2D for mutations in GARS gene. In addition, we conducted a study of possible GARS involvement in patients with juvenile-onset muscular atrophy of the distal upper extremity classified as Hirayama disease. Our conclusion is that GARS was not a factor in the etiology of Hirayama disease in this specific cohort. 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识别和表征与遗传性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：我们先前已经确定结蛋白基因(DES)是引起心脏和骨骼肌病的原因。到目前为止，该基因的52个突变已被证明是致病的。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，有62%是结蛋白基因突变导致了这种疾病。剩下的38%现在与其他四个基因的突变有关，MYOT占28%，ZASP占3%，CryAB和Flc各占1%，5%的患者有超过一个基因的突变。我们的分析在这些遗传亚型之间建立了足够的临床、电生理和肌肉病理学相似性，从而将它们归类为肌纤维肌病。同时，我们发现了在诊断和针对亚型的治疗和管理中应该考虑的遗传多样性亚型之间的显著表型差异。 线状肌病：我们重新分析了四个家系的NEM6候选区域，并确定致病基因位于染色体15q22.31上6.7兆碱基的区域。对该区域多个基因的筛选发现了一个未知的KBTBD13基因，该基因编码一个编码458个氨基酸的KBTBD13蛋白外显子，在骨骼肌和心肌中表达的相对分子质量为49 kDa。蛋白质结构分析将KBTBD13归类为BTB/Kelch超家族成员。KBTBD13在骨骼肌中的功能作用和线虫性肌病的发病机制有待进一步研究。 Charcot-Marie牙病2D型和脊肌萎缩症V型：我们先前已经确定甘氨酰-tRNA合成酶(GARS)基因突变是常染色体显性遗传性运动性远端神经元病/轴索病的原因。我们现在测试了一组被推定为CMT2D的散发性患者的GARS基因突变。此外，我们还进行了一项关于上肢远端幼年型肌萎缩症患者可能参与GARS的研究，这些患者被归类为平山病。我们的结论是，在这一特定队列中，GARS不是平山病病因的一个因素。 特发性震颤基因的染色体定位：此前，我们在两个美国家系中报道了6p23上的一个新的有希望的染色体座位，并将另外三个家系中的疾病基因定位到染色体11p15上的另一个座位上。我们现在已经使用新的生理学和基因分型技术重新评估了一个没有显示与这些基因座连锁的当地大家庭。我们现在正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：我们分析了东西伯利亚VILUISK脑脊髓炎疫情的年发病率和其他特征，使用了大量临床和病理确诊患者的数据集。在疫情高峰期，年平均发病率达到每10万人8.8人，主要影响年轻人。最初的疫情发生在Viliui中部地区，后来蔓延到邻近地区，最终蔓延到人口更稠密的西南部地区和首都雅库茨克附近的中部地区的偏远地区，当地人口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。据推测，最近的社会和人口变化有助于疾病发病率的下降。