DF/HCC Program Affiliation

Cancer Genetics

Research Abstract

The muscular dystrophies are progressive disorders of striated muscle leading to breakdown of muscle integrity. Underlying this clinical presentation there is considerable genetic heterogeneity with the X-chromosomal recessive Duchenne and Becker forms comprising the majority of patients, and the related limb girdle muscular dystrophies (LGMD) being caused by an additional 10 different genetic loci. Much has been learned over the last 12 years about the molecular defects associated with the muscular dystrophies, beginning with the identification of dystrophin as the protein altered in Duchenne/Becker muscular dystrophy. Dystrophin has since been shown to be part of a complex of proteins at the muscle cell membrane known as the dystrophin associated protein (DAP) complex. Five other protein members of this complex are themselves encoded by genes that are disrupted in LGMD patients. The exact mechanism by which the muscle cell undergoes degeneration when this complex is disturbed is unknown. To date there is no known way to halt the muscle cell degeneration when this complex is perturbed, although animal studies have shown that introduction of the normal gene into diseased muscle is corrective for the problem. We continue our two broad areas of research to address the pathogenesis and treatment of the muscular dystrophies. The first is a continuation of our efforts to unravel the normal function of the dystrophin associated protein complex and why alteration of genes encoding members of the complex causes the phenotype of muscular dystrophy. The second is our continuing effort to develop a stem cell-based therapy for treatment of patients with muscular dystrophy. Both broad areas are driven by our hope to be curative for the muscular dystrophies.

Publications

• Kohane IS, Mandl KD, Taylor PL, Holm IA, Nigrin DJ, Kunkel LM.Medicine. Reestablishing the researcher-patient compact.Science 2007 May 11;316(5826):836-7.
  17495156
• Mizuno Y, Guyon JR, Ishii A, Hoshino S, Ohkoshi N, Tamaoka A, Okamoto K, Kunkel LM.Beta-synemin expression in cardiotoxin-injected rat skeletal muscle.BMC Musculoskelet Disord 2007;8:40.
  17493272
• Péault B, Rudnicki M, Torrente Y, Cossu G, Tremblay JP, Partridge T, Gussoni E, Kunkel LM, Huard J.Stem and Progenitor Cells in Skeletal Muscle Development, Maintenance, and Therapy.Mol Ther 2007 May;15(5):867-877.
  17387336
• Steffen LS, Guyon JR, Vogel ED, Beltre R, Pusack TJ, Zhou Y, Zon LI, Kunkel LM.Zebrafish orthologs of human muscular dystrophy genes.BMC Genomics 2007;8:79.
  17374169
• Guyon JR, Steffen LS, Howell MH, Pusack TJ, Lawrence C, Kunkel LM.Modeling human muscle disease in zebrafish.Biochim Biophys Acta 2007 Feb;1772(2):205-15.
  16934958
• Dalkilic I, Schienda J, Thompson TG, Kunkel LM.Loss of FilaminC (FLNc) results in severe defects in myogenesis and myotube structure.Mol Cell Biol 2006 Sep;26(17):6522-34.
  16914736
• Duncan DR, Kang PB, Rabbat JC, Briggs CE, Lidov HG, Darras BT, Kunkel LM.A novel mutation in two families with limb-girdle muscular dystrophy type 2C.Neurology 2006 Jul 11;67(1):167-9.
  16832103
• Bachrach E, Perez AL, Choi YH, Illigens BM, Jun SJ, del Nido P, McGowan FX, Li S, Flint A, Chamberlain J, Kunkel LM.Muscle engraftment of myogenic progenitor cells following intraarterial transplantation.Muscle Nerve 2006 Jul;34(1):44-52.
  16634061
• Kho AT, Kang PB, Kohane IS, Kunkel LM.Transcriptome-scale similarities between mouse and human skeletal muscles with normal and myopathic phenotypes.BMC Musculoskelet Disord 2006 Mar 7;7(1):23.
  16522209
• Schienda J, Engleka KA, Jun S, Hansen MS, Epstein JA, Tabin CJ, Kunkel LM, Kardon G.Somitic origin of limb muscle satellite and side population cells.Proc Natl Acad Sci U S A 2006 Jan 24;103(4):945-50.
  16418263