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.

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Kley, Rudolf A; van der Ven, Peter F M; Olive, Montse et al. (2013) Impairment of protein degradation in myofibrillar myopathy caused by FLNC/filamin C mutations. Autophagy 9:422-3
Toro, Camilo; Olive, Montse; Dalakas, Marinos C et al. (2013) Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins. BMC Neurol 13:29
Furst, Dieter O; Goldfarb, Lev G; Kley, Rudolf A et al. (2013) Filamin C-related myopathies: pathology and mechanisms. Acta Neuropathol 125:33-46
Blumen, Sergiu C; Drory, Vivian E; Sadeh, Menachem et al. (2010) Mutational analysis of glycyl-tRNA synthetase (GARS) gene in Hirayama disease. Amyotroph Lateral Scler 11:237-9
Pinol-Ripoll, Gerard; Shatunov, Alexey; Cabello, Ana et al. (2009) Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin. Neuromuscul Disord 19:418-22
McNeill, Alisdair; Birchall, Daniel; Straub, Volker et al. (2009) Lower limb radiology of distal myopathy due to the S60F myotilin mutation. Eur Neurol 62:161-6
Shatunov, Alexey; Olive, Montse; Odgerel, Zagaa et al. (2009) In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy. Eur J Hum Genet 17:656-63
Gamez, Josep; Armstrong, Judith; Shatunov, Alexey et al. (2009) Generalized muscle pseudo-hypertrophy and stiffness associated with the myotilin Ser55Phe mutation: a novel myotilinopathy phenotype? J Neurol Sci 277:167-71
Goldfarb, Lev G; Vladimirtsev, Vsevolod A; Platanov, Fyodor A et al. (2009) Viliuisk encephalomyelitis in Eastern Siberia - analysis of 390 cases. Folia Neuropathol 47:171-81
Goldfarb, Lev G; Dalakas, Marinos C (2009) Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest 119:1806-13

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