Uniformed Services University of the Health Sciences
Department of Anesthesiology
4301 Jones Bridge Road, C1094
Bethesda, Maryland 20814-4799
Phone: (301) 295-3683
FAX: (301) 295-1996
Genetics, Vavilov Institute of General Genetics, Moscow, Russia
Postdoctoral, Clinical Neurogenetics, NINDS, NIH
Molecular and genetic mechanisms of inherited muscle disorders in human
The focus of my research is to elucidate the etiology and pathogenic mechanisms of inherited muscle disorders, particularly diseases of thin filament and Calcium regulation in muscle. Our laboratory approaches this goal through study of cellular and molecular mechanisms using a broad range of techniques including cell culture, mutation analysis and in vitro gene knockdown.
Disease of muscle thin filament:
Nemaline myopathies (NEM), a group of clinically and genetically heterogeneous muscle disorders characterized by an accumulation of thin filament proteins into rod-like aggregates (nemaline bodies) in affected muscle fibers. To-date, mutations in six genes associated with NEM. All these genes encode structural proteins that are components of actin filament and hence NEM is considered a disease of muscle thin filament. NEM associated abnormalities appear to affect sarcomere organization through structural disruption of thin filament. Recently, we have identified a novel gene named Kelch- repeat and BTB (POZ) domain containing 13 (KBTBD13) that if mutated cause a subtype of NEM. We are launching a research to find fundamental and novel aspects of disease mechanisms in NEM and of muscle thin filament regulation. The objectives of our current studies include development of a novel in vitro model to characterize KBTBD13 function in muscle, identification of muscle proteins interacting with KBTBD13 and determination of muscle thin filament regulation by KBTBD13.
Disease of Calcium regulation:
Malignant Hyperthermia (MH) is pharmacogenetic disorder triggered as a life-threatening metabolic crisis upon administration of anesthetics. Our studies concentrate on the characterization of genetic defects in skeletal muscle calcium homeostasis governed by proteins regulating excitation contraction coupling. The Ryanodine receptor type 1 gene (RYR1) coding for the skeletal muscle specific intracellular calcium channel plays a central role in muscle contraction. The group of neuromuscular disorders caused by defects in excitation contraction coupling currently include, in addition to MH, Central core disease, Multi-mini core disease, Exertional heat illness, and Exercise-induced rhabdomyolisis. We are characterizing families segregating these disorders and conducting studies in order to identify the mutational spectrum, to search and characterize new genes in MH.
Kolman CJ, Sambuughin N, Bermingham E. Mitochondrial DNA analysis of Mongolian populations and implications for the origin of New World founders. Genetics 1996;142:1321-34.
Lee HS, Sambuughin N, Cervenakova L, Chapman J, Pocchiari M, Litvak S, Qi HY, Budka H, del Ser T, Furukawa H, Brown P, Gajdusek DC, Long JC, Korczyn AD, Goldfarb LG. Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease. Am J Hum Genet 1999;64:1063-1070.
Sivakumar K, Sambuughin N, Selenge B, Nagle JW, Baasanjav D, Hudson LD, Goldfarb LG. Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members. Ann Neurol 1999;45:680-683.
Sambuughin N, McWilliams S, de Bantel A, Sivakumar K, Nelson TE. Deletion in the RYR1 gene associated with unusual contraction phenotype in Malignant Hyperthermia. Am J Hum Genet 2001; 69:204-8.
Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ et al. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal Spinal Muscular Atrophy type V. Am J Hum Genet 2003; 72:1293-1299.
Sambuughin N, Holley H, H, Muldoon S, Brandom BW, de Bantel AM, Tobin JR, Nelson TE, Goldfarb LG. Screening of the Entire Ryanodine Receptor Type 1 Coding Region for Sequence Variants Associated with Malignant Hyperthermia Susceptibility in the North American Population. Anesthesiology 2005; 102: 515-521.
Shatunov A, Sambuughin N, Jankovic J, Elble R, Lee HS, Singleton AB, Dagvadorj A, Ji J, Zhang Y, Kimonis VE, Hardy J, Hallett M, Goldfarb LG. Genomewide scans in North-American families reveal genetic linkage of essential tremor to a region on chromosome 6p23. Brain 2006; 129:2318-2331.
Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, Bina S, Muldoon S. The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet 2009, 76: 1218-1224.
Sambuughin N, Yau KS, Oliv? M, Duff RM, Bayarsaikhan M, Lu S, Gonzalez-Mera L, Sivadorai P, Nowak KJ, Ravenscroft G, Mastaglia FL, North KN, Ilkovski B, Kremer H, Lammens M, van Engelen BG, Fabian V, Lamont P, Davis MR, Laing NG, Goldfarb LG. Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. Am J Hum Genet. 2010; 87: 842-7.