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：
7969578
负责人：
Lev G Goldfarb
金额：
$ 93.14万
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/7969578
关键词：
11p15 6p23 Adolescent Affect Age Amendment American Biopsy Specimen Candidate Disease Gene Cardiac Charcot-Marie-Tooth Disease Chromosome Mapping Chromosomes Clinical Clinical Protocols Code Collaborations Defect Desmin Diagnosis Diagnostic Diagnostic Procedure Disease Distal Dystonia Essential Tremor Etiology Family Family member Future Gene Mutation Genes Genetic Genetic Transcription Genetic screening method Genotype Glycine-tRNA Ligase Goals Guidelines Hispanic Americans Inherited Laboratories Link Lod Score Molecular Molecular Analysis Motor Movement Muscle Muscular Atrophy Mutation Mutation Detection Myoclonus Myopathy National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neuromuscular Diseases Neurosciences Pathogenesis Pathogenicity Patients Phenotype Physical Chromosome Mapping Reporting Research Services Single Nucleotide Polymorphism Spinal Muscular Atrophy Testing Time Tissue Sample Upper Extremity Variant axonopathy cohort density follow-up improved nervous system disorder neurogenetics programs skeletal

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 as the cause of cardiac and skeletal myopathies. To-date, 45 mutations in this gene have been proven pathogenic. New studies conducted in this laboratory have shown that mutations in desmin gene caused the disease in only 62% of 147 patients with a definite diagnosis of myofibrillar myopathy we have studied over the year. The remaining 33% 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 identified subtypes that should be considered in future studies of disease pathogenesis, and used for optimization of subtype-specific treatments and management. 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, and, in addition, conducted a study of possible GARS involvement in patients with juvenile-onset muscular atrophy of the distal upper extremity classified as Hirayamas disease. Our preliminary conclusion was that GARS was not a factor in the etiology of Hirayamas disease in this specific cohort. CHROMOSOMAL MAPPING OF GENES CAUSING ESSENTIAL TREMOR: Essential tremor is the most common neurological disease affecting 4 to 6% of people at the age older than 40. Previously, we reported a new promising locus on chromosome 6p23 in two American families. We have now tested for mutations 14 candidate genes located in the 600-kB linked region. Some sequence variants are under study. Two other families, American and Spanish, show linkage to a different locus on chromosome 11p15 with LOD score of 2.45 spanning 9 cM, which suggests that more than one or even two genes are likely to be responsible for familial Essential tremor. High density single nucleotide polymorphism genotyping did not improve the LOD score but was able to narrow the linked region to 3.5 cM. We tested candidate genes in this region, which are functionally relevant. We sequenced coding regions of SYT8 and KCNQ1DN genes and demonstrated that RNA expression level of another candidate gene, DRD4, was increased in a muscle biopsy sample from one of the patients. We are planning to follow up on these results by examining more genes and additional tissue samples from affected family members.

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基因确定为心脏和骨骼肌病的原因。迄今为止，该基因中的45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该疾病在147名患者中只有62％的肌原纤维肌病确定诊断为我们一年中研究。其余的33％现在与其他四个基因的突变相关，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。我们的分析确定了这些多样的遗传亚型之间的足够的临床，电生理和肌病学相似性，使它们可以将其归类为肌原纤维肌病。同时，我们发现了在疾病发病机理的未来研究中应考虑的基因鉴定的亚型之间的实质性表型区别，并用于优化亚型特异性治疗和管理。 Charcot-Marie-Tooth疾病2D型和脊髓肌肉萎缩V型：我们先前已经鉴定出甘油型TRNA合成酶（GARS）基因突变是常染色体显性运动远端神经疾病/轴突病的原因。现在，我们测试了一组散发性诊断为CMT2D的散发性患者，用于GARS基因突变，此外，还研究了对远端上肢远端上肢的少年发作肌肉萎缩的患者可能受累的GARS参与。我们的初步结论是，在这种特定队列中，GARS并不是广场疾病病因的一个因素。引起基本震颤的基因的染色体图：基本震颤是影响40岁以上年龄的4至6％的最常见的神经系统疾病。以前，我们报道了两个美国家庭中6p23染色体的新有希望的基因座。现在，我们已经测试了位于600 kb链接区域的突变14个候选基因。一些序列变体正在研究中。其他两个家庭，即美国和西班牙，在11p15染色体上显示了与不同的基因座的联系，LOD得分为2.45，跨度为9厘米，这表明多个或两个基因可能是家庭基本震颤的原因。高密度的单核苷酸多态性基因分型不能提高LOD评分，而是能够将关联区域缩小到3.5 cm。我们测试了该区域中与功能相关的候选基因。我们对SYT8和KCNQ1DN基因的编码区进行了测序，并证明了另一个患者的肌肉活检样本中，另一个候选基因DRD4的RNA表达水平增加。我们计划通过检查受影响家庭成员的更多基因和其他组织样本来跟进这些结果。