BADERC- James Gusella

James Gusella, Ph.D.

Genetics Research Cycle in Human Disease

The major focus in Dr. Gusella’s laboratory, and by extension the rest of the new Center for Human Genetic Research at the MGH is 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, 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. Gusella JF, MacDonald ME. Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease. Nature Rev Neurosci 2000; 1: 109-115.

2. Gusella JF, MacDonald ME. No post-genetics era in human disease research. Nature Rev Genet 2002; 3, 72-29.

3. Wheeler VC, Gutekunst CA, Vrbanac V, Lebel LA, Schilling G, Hersch S, Friedlander RM, Gusella JF, Vonsattel JP, Borchelt DR, MacDonald ME. Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Hum Mol Genet 2002; 11:633-40.

4. DeStefano AL, Lew MF, Golbe LI, Mark MH, Lazzarini AM, Guttman M, Montgomery E, Waters CH, Singer C, Watts RL, Currie LJ, Wooten GF, Maher NE, Wilk JB, Sullivan KM, Slater KM, Saint-Hilaire MH, Feldman RG, Suchowersky O, Lafontaine AL, Labelle N, Growdon JH, Vieregge P, Pramstaller PP, Klein C, Hubble JP, Reider CR, Stacy M, MacDonald ME, Gusella JF, Myers RH. PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. Am J Hum Genet 2002; 70:1089-95

5. Slaugenhaupt SA, Gusella JF. Familial dysautonomia. Curr Opin Genet Dev 2002; 12:307-11.

6. Fossale E, Wheeler VC, Vrbanac V, Lebel LA, Teed A, Mysore JS, Gusella JF, MacDonald M, Persichetti F. Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice. Hum Mol Genet 2002; 11:2233-41.

7. Cuajungco MP, Leyne M, Mull J, Gill SP, Lu W, Zagzag D, Axelrod FB, Maayan C, Gusella JF, Slaugenhaupt SA. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am J Hum Genet 2003;72:

8. Takano H, Gusella JF. The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci 2002; 3:15.

9. Gines S, Seong IS, Fossale E, Ivanova E, Trettel F, Gusella JF, Wheeler VC, Persichetti F, MacDonald ME. Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Hum Mol Genet 2003;12:497-508.






			James Gusella, Ph.D. Genetics Research Cycle in Human Disease The major focus in Dr. Gusella’s laboratory, and by extension the rest of the new Center for Human Genetic Research at the MGH is 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, 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. Gusella JF, MacDonald ME. Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease. Nature Rev Neurosci 2000; 1: 109-115. 2. Gusella JF, MacDonald ME. No post-genetics era in human disease research. Nature Rev Genet 2002; 3, 72-29. 3. Wheeler VC, Gutekunst CA, Vrbanac V, Lebel LA, Schilling G, Hersch S, Friedlander RM, Gusella JF, Vonsattel JP, Borchelt DR, MacDonald ME. Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Hum Mol Genet 2002; 11:633-40. 4. DeStefano AL, Lew MF, Golbe LI, Mark MH, Lazzarini AM, Guttman M, Montgomery E, Waters CH, Singer C, Watts RL, Currie LJ, Wooten GF, Maher NE, Wilk JB, Sullivan KM, Slater KM, Saint-Hilaire MH, Feldman RG, Suchowersky O, Lafontaine AL, Labelle N, Growdon JH, Vieregge P, Pramstaller PP, Klein C, Hubble JP, Reider CR, Stacy M, MacDonald ME, Gusella JF, Myers RH. PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. Am J Hum Genet 2002; 70:1089-95 5. Slaugenhaupt SA, Gusella JF. Familial dysautonomia. Curr Opin Genet Dev 2002; 12:307-11. 6. Fossale E, Wheeler VC, Vrbanac V, Lebel LA, Teed A, Mysore JS, Gusella JF, MacDonald M, Persichetti F. Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice. Hum Mol Genet 2002; 11:2233-41. 7. Cuajungco MP, Leyne M, Mull J, Gill SP, Lu W, Zagzag D, Axelrod FB, Maayan C, Gusella JF, Slaugenhaupt SA. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am J Hum Genet 2003;72: 8. Takano H, Gusella JF. The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci 2002; 3:15. 9. Gines S, Seong IS, Fossale E, Ivanova E, Trettel F, Gusella JF, Wheeler VC, Persichetti F, MacDonald ME. Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Hum Mol Genet 2003;12:497-508.