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: 8746783
• 负责人: Lev G Goldfarb
• 金额: $ 10.58万
• 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/8746783
• 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; Services; Siberia; Skeletal Muscle; Techniques; Therapeutic Intervention; Time; exome sequencing; genetic analysis; genetic pedigree; human migration; improved; member; molecular mass; neurogenetics; physical mapping; programs; protein structure; screening; 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，从而将其归类为肌原纤维性肌病。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。 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些位点，通过使用新的生理学和基因分型技术。我们现在使用外显子组测序进行候选基因检测。有关研究正在进行中。 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。

项目成果

Global distribution of fatal familial insomnia: founder or recurrent mutations.

致命性家族性失眠的全球分布：创始人或复发突变。

• DOI: 10.1007/s10048-008-0135-3
• 发表时间: 2008
• 期刊: Neurogenetics
• 影响因子: 2.2
• 作者: Lee,H-S;Goldfarb,LG
• 通讯作者: Goldfarb,LG

Novel FLNC mutation in a patient with myofibrillar myopathy in combination with late-onset cerebellar ataxia.

• DOI: 10.1002/mus.23349
• 发表时间: 2012-08
• 期刊: MUSCLE & NERVE
• 影响因子: 3.4
• 作者: Tasca, Giorgio;Odgerel, Zagaa;Monforte, Mauro;Aurino, Stefania;Clarke, Nigel F.;Waddell, Leigh B.;Udd, Bjarne;Ricci, Enzo;Goldfarb, Lev G.
• 通讯作者: Goldfarb, Lev G.

Genetic variants in potassium channels are associated with type 2 diabetes in a Mongolian population.

• DOI: 10.1111/j.1753-0407.2011.00177.x
• 发表时间: 2012-09
• 期刊: Journal of diabetes
• 影响因子: 4.5
• 作者: Odgerel Z;Lee HS;Erdenebileg N;Gandbold S;Luvsanjamba M;Sambuughin N;Sonomtseren S;Sharavdorj P;Jodov E;Altaisaikhan K;Goldfarb LG
• 通讯作者: Goldfarb LG

KBTBD13 interacts with Cullin 3 to form a functional ubiquitin ligase.

• DOI: 10.1016/j.bbrc.2012.04.074
• 发表时间: 2012-05-18
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Sambuughin N;Swietnicki W;Techtmann S;Matrosova V;Wallace T;Goldfarb L;Maynard E
• 通讯作者: Maynard E

Mutational analysis of glycyl-tRNA synthetase (GARS) gene in Hirayama disease.

平山病甘氨酰-tRNA 合成酶 (GARS) 基因突变分析。

• DOI: 10.3109/17482960902849823
• 发表时间: 2010
• 期刊: Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases
• 作者: Blumen,SergiuC;Drory,VivianE;Sadeh,Menachem;El-Ad,Baruch;Soimu,Uri;Groozman,GalinaB;Bouchard,Jean-Pierre;Goldfarb,LevG
• 通讯作者: Goldfarb,LevG