Genetics Research Cycle in Human Disease

The major focus in Dr. Gusella’s laboratory, and by extension the rest of the Center for Human Genetic Research at the MGH continues to be the pursuit of the genetic research cycle in a variety of human disorders. This cycle involves: a) using patient samples/phenotypes (clinical, biochemical, molecular, etc.) to relate differences in human genotype with phenotypic variation (normal variation, disease causative differences, predisposing variants, modifying genes, developmental variants, determinants of response to therapy, “physiologic genomics”), b) using biochemistry, cell biology, lower organisms and especially mouse modeling to understand mechanisms and interactions operative in both disease and normal physiology, c) using genetics in the mouse and other organisms as a powerful route to lead the way to genes that may be important in humans for either normal biology or disease pathogenesis, and d) pursuing translational efforts to use the genetic findings to deliver better diagnostics, management and treatment to patients. In addition to collaborating widely to facilitate the genetic research cycle for members of other departments, including genetic studies of diabetes and endocrine dysfunction, Dr. Gusella’s laboratory investigates inherited nervous system disorders such as Huntington’s disease, Parkinson’s disease, autism, familial dysautonomia, and neurofibromatosis. Of particular relevance to diabetes are the findings that mutation in familial dysautonomia offers a clear model of tissue-specific control of splicing in human disease, and that mouse models of HD expressing expanded polyglutamine protein develop diabetic symptoms, providing a novel route to discovering genetic modifiers in this disorder.

References:

1. Slaugenhaupt SA, Mull J, Leyne M, Cuajungco MP, Gill SP, Hims MM, Quintero F, Axelrod FB, Gusella JF. Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Hum Mol Genet.  2004; 13:429-36. Epub 2004 Jan 06
   
   
2. Wang J, Gines S, Macdonald ME, Gusella JF. Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci. 2005 Jan 13;6:1.
   
   
3. Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, MacDonald ME.  HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet. 2005; 14:2871-80.
   
   
4. Li JL, Hayden MR, Warby SC, Durr A, Morrison PJ, Nance M, Ross CA, Margolis RL, Rosenblatt A, Squitieri F, Frati L, Gomez-Tortosa E, Garcia CA, Suchowersky O, Klimek ML, Trent RJ, McCusker E, Novelletto A, Frontali M, Paulsen JS, Jones R, Ashizawa T, Lazzarini A, Wheeler VC, Prakash R, Xu G, Djousse L, Mysore JS, Gillis T, Hakky M, Cupples LA, Saint-Hilaire MH, Cha JH, Hersch SM, Penney JB, Harrison MB, Perlman SL, Zanko A, Abramson RK, Lechich AJ, Duckett A, Marder K, Conneally PM, Gusella JF, Macdonald ME, Myers RH.  Genome-wide Significance for a Modifier of Age at Neurological Onset in Huntington Disease at 6q23-24: the HD MAPS Study. BMC Med Genet. 2006; 7:71.
   
   
5. Hims MM, Ibrahim el C, Leyne M, Mull J, Liu L, Lazaro C, Shetty RS, Gill S, Gusella JF, Reed R, Slaugenhaupt SA.  Therapeutic potential and mechanism of kinetin as a treatment for the human splicing disease familial dysautonomia. J Mol Med. 2007;85:149-61.