Genotype-Phenotype Correlations In Movement and Neuromuscular Disorders

临床神经遗传学研究计划的重点是识别和表征参与遗传性运动和神经肌肉疾病的基因和遗传机制。 肌纤维性肌病：我们以前已经确定结蛋白基因（DES）是心脏和骨骼肌病变的原因。迄今为止，该基因中的52个突变已被证明是致病的。本实验室进行的最新研究表明，结蛋白基因突变导致147例确诊为肌原纤维性肌病的患者中有62%的疾病。剩下的38%现在与其他四个基因的突变有关，MYOT为28%，ZASP为3%，ESTAB和FLNC各为1%，5%的患者在一个以上的基因中发生突变。我们的分析在这些不同的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，允许将其分类为肌原纤维肌病。与此同时，我们发现了在诊断和亚型特异性治疗和管理中应该考虑的遗传多样性亚型之间的实质性表型差异。 内马林肌病：我们重新分析了四个家系的NEM 6候选区域，并确定致病基因位于染色体15q22.31上的6.7兆碱基区域。在这一领域的多个基因的筛选导致在以前未知的KBTBD 13基因的鉴定，包含一个单一的外显子编码的KBTBD 13蛋白的458个氨基酸和49 kDa的分子量表达在骨骼肌和心肌。蛋白质结构分析允许将KBTBD 13分类为BTB/Kelch超家族的成员。KBTBD 13在骨骼肌中的功能作用和线虫性肌病的发病机制是进一步研究的主题。 腓骨肌萎缩症2D型和脊肌萎缩症V型：我们以前已经确定甘氨酰-tRNA合成酶（加尔斯）基因突变是常染色体显性运动远端神经元病/轴突病的病因。我们现在检测了一组假定诊断为CMT 2D的散发患者的加尔斯基因突变。此外，我们进行了一项研究，可能加尔斯参与的患者与青少年发病的肌肉萎缩的远端上肢归类为平山病。我们的结论是加尔斯不是这个特定队列中平山病病因的一个因素。 染色体定位的基因引起的本质震颤：以前，我们报告了一个新的有希望的染色体位点6p 23在两个美国家庭和映射的疾病基因在其他三个家庭的另一个位点染色体11 p15。我们现在已经重新评估了一个大的本地家庭，没有显示出连锁的任何这2个位点，通过使用新的生理技术。在表型分析过程完成后，我们计划使用外显子组测序进行候选基因检测。 VILYUISK脑脊髓炎：我们分析了东西伯利亚维留伊斯克脑脊髓炎流行的年发病率和其他特征，使用了大量临床和病理确诊的患者数据集。在流行病高峰期，年平均发病率达到每100 000人8.8例，主要是年轻人。最初的疫情发生在中部维留伊地区，后来蔓延到邻近地区，最终蔓延到人口更密集的西南地区和首都雅库茨克附近的中部地区，当地人口中出现了许多新病例。结果表明，从流行村庄的人口迁移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。

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 diverse 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 Hirayamas disease. Our conclusion is that GARS was not a factor in the etiology of Hirayamas 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 2 loci by using newer physiology techniques. After the phenotyping process is completed, we are planning to use exome sequencing for candidate gene detection. 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.