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是心脏和骨骼肌病变的原因。迄今为止，该基因中的45个突变已被证明是致病的。在本实验室进行的新研究表明，结蛋白基因突变导致的疾病，只有62%的147例明确诊断的肌原纤维肌病，我们已经研究了一年。剩下的33%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，允许将其归类为肌原纤维肌病;同时，我们发现了在未来的疾病发病机制研究中应考虑的遗传鉴定亚型之间的实质性表型差异，并用于优化亚型特异性治疗和管理。 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。现在，我们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，我们还对归类为平山病的青少年型上肢远端肌萎缩患者可能涉及的加尔斯进行了研究。我们的初步结论是，在这个特定的队列中，加尔斯不是平山病的病因学因素。 原发性震颤基因的染色体定位：原发性震颤是最常见的神经系统疾病，影响4%至6%的40岁以上的人。以前，我们报道了一个新的有希望的基因座染色体6p 23在两个美国家庭。我们现在已经测试了位于600 kB连锁区域的14个候选基因的突变。一些序列变异正在研究中。另外两个家庭，美国和西班牙，显示连锁到染色体11 p15上的不同位点，LOD评分为2.45，跨越9 cM，这表明超过一个甚至两个基因可能是导致家族性特发性震颤的原因。高密度单核苷酸多态性基因分型并没有提高LOD评分，但能够将连锁区域缩小到3.5 cM。我们测试了该区域的候选基因，这些基因在功能上是相关的。我们对SYT 8和KCNQ 1DN基因的编码区进行了测序，并证明了另一个候选基因DRD 4的RNA表达水平在其中一名患者的肌肉活检样本中增加。我们计划通过检查更多的基因和受影响家庭成员的额外组织样本来跟进这些结果。

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.