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是引起心脏和骨骼肌病的原因。到目前为止，该基因的45个突变已被证明是致病的。在这个实验室进行的新研究表明，在我们一年来研究的147名确诊为肌纤维肌病的患者中，只有62%的人是由结蛋白基因突变导致的。剩下的33%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，从而将它们归类为肌纤维肌病；同时，我们发现了遗传识别的亚型之间的显著表型差异，这些表型差异应该在未来的疾病发病机制研究中考虑，并用于优化亚型特异性的治疗和管理。 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患者可能参与GARS的研究，这些患者被归类为平山病。我们的初步结论是，在这个特定的队列中，GARS不是平山病的病因学因素。 引起特发性震颤的基因的染色体图谱：特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。此前，我们在两个美国家系中报道了染色体6p23上的一个新的有希望的基因座。我们现在已经测试了位于600kB连接区的14个候选基因的突变。一些序列变体正在研究中。另外两个家系，美国人和西班牙人，与染色体11p15上的一个不同的基因连锁，LOD评分为2.45，跨越9 cM，这表明可能有不止一个甚至两个基因与家族性特发性震颤有关。高密度单核苷酸多态基因分型不能提高LOD评分，但能将连锁区域缩小到3.5 cM。我们测试了这一区域的候选基因，它们在功能上是相关的。我们对SYT8和KCNQ1DN基因的编码区进行了测序，并证明在其中一名患者的肌肉活检样本中，另一候选基因DRD4的RNA表达水平增加。我们正计划通过检查更多的基因和来自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.