Genotype-Phenotype Correlations In Movement and Neuromuscular Disorders

临床神经遗传学研究项目的重点是遗传运动和神经肌肉疾病中涉及的基因和遗传机制的鉴定和表征。

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.