James Gusella

Department of Genetics
Center for Human Genetic Research
Massachusetts General Hospital
Richard B. Simches Research Center CPZ 5280
185 Cambridge St.
Boston, MA 02114
Tel: (617) 726-5724
Fax: (617) 726-5735
Email: gusella@helix.mgh.harvard.edu
Web Page: The Gusella Lab Page

My laboratory is focused on understanding nervous system disease using molecular genetic strategies, beginning with human patients and proceeding through in vitro and modeling studies. Our goal is to improve diagnosis, management and treatment of dedicated to the exploration of inherited disorders of the nervous system using primarily a molecular biological approach. In any given disorder, the research can usually be divided into four sequential stages:

1. Determination of the chromosomal location of a gene defect, susceptibility gene or genetic modifier, usually based on linkage or association studies with polymorphic genetic markers.

2. Identification of the gene responsible for the phenotypic effect based upon its chromosomal location using a variety of genome analysis strategies.

3. Characterization of the mechanism of action based upon analysis of the allelic versions of the culprit gene in man, and in appropriate in vitro or in vivo model systems, such as creation of transgenic mouse models, analysis of existing animal models, expression of gene products in cultured cells, and genetic analysis in Drosophila and other model organisms.

4. Exploration of the potential for rational therapies, including genetic therapies.

We are currently searching for susceptibility and modifier genes in Parkinson's disease and Huntington's disease, and, as part of the Developmental Genome Anatomy Project, identifying genes at the breakpoints of balanced translocations associated with developmental abnormality. We are also examining the mechanism of pathogenesis of genetic defects in biotin-responsive basal ganglia disease, Huntington's disease, neurofibromatosis, and torsion dystonia and pursuing assays to identify genetic or chemical modifiers in some of these disorders, with the ultimate goal of developing an effective rational therapy. Finally, we are involved in efforts to apply both morphometric and functional imaging studies aimed at providing novel phenotypes for analysis of the genetic underpinnings of behavior and cognition.

References:

• Kim HG, Herrick SR, Lemyre E, Kishikawa S, Salisz JA, Seminara S, MacDonald ME, Bruns GA, Morton CC, Quade BJ, Gusella JF. Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1. J Med Genet. 2005 Aug;42(8):666-72.
• Zeng WQ, Al-Yamani E, Acierno JS Jr, Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella JF. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet. 2005 Jul;77(1):16-26. Epub 2005 May 3.
• 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):1.
• Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, Dode C, Morrison PJ, Suchowersky O, Ross CA, Margolis RL, Rosenblatt A, Gomez-Tortosa E, Cabrero DM, Novelletto A, Frontali M, Nance M, Trent RJ, McCusker E, Jones R, Paulsen JS, Harrison M, Zanko A, Abramson RK, Russ AL, Knowlton B, Djousse L, Mysore JS, Tariot S, Gusella MF, Wheeler VC, Atwood LD, Cupples LA, Saint-Hilaire M, ChaJH, Hersch SM, Koroshetz WJ, Gusella JF, MacDonald ME, Myers RH.  A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. Am J Hum Genet. 2003 Sep;73(3):682-7. Epub 2003 Aug 1.