James Gusella headshot
James Francis Gusella, Ph.D.
Bullard Professor of Neurogenetics in the Department of Genetics

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, with the ultimate goal of improving diagnosis, management and treatment.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, including cultured human cells, genetically engineered mice, and lower organisms such as Drosophila and Dictyostelium.
4. Exploration of the potential for rational therapies, including genetic therapies.

We are currently searching for susceptibility and modifier genes in autism, Parkinson's disease, and Huntington's disease. As part of the Developmental Genome Anatomy Project, we also identify genes at breakpoints of balanced translocations associated with developmental abnormality. Finally we are examining the mechanism of pathogenesis of genetic defects in autism, biotin-responsive basal ganglia disease, Huntington's disease, Parkinson's disease, and neurofibromatosis, and pursuing assays to identify genetic and chemical modifiers, with the ultimate goal of contributing to effective rational therapies.

Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset.
Authors: Authors: McAllister B, Donaldson J, Binda CS, Powell S, Chughtai U, Edwards G, Stone J, Lobanov S, Elliston L, Schuhmacher LN, Rees E, Menzies G, Ciosi M, Maxwell A, Chao MJ, Hong EP, Lucente D, Wheeler V, Lee JM, MacDonald ME, Long JD, Aylward EH, Landwehrmeyer GB, Rosser AE, Paulsen JS, Williams NM, Gusella JF, Monckton DG, Allen ND, Holmans P, Jones L, Massey TH.
Nat Neurosci
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Genetic modifiers of Huntington disease differentially influence motor and cognitive domains.
Authors: Authors: Lee JM, Huang Y, Orth M, Gillis T, Siciliano J, Hong E, Mysore JS, Lucente D, Wheeler VC, Seong IS, McLean ZL, Mills JA, McAllister B, Lobanov SV, Massey TH, Ciosi M, Landwehrmeyer GB, Paulsen JS, Dorsey ER, Shoulson I, Sampaio C, Monckton DG, Kwak S, Holmans P, Jones L, MacDonald ME, Long JD, Gusella JF.
Am J Hum Genet
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Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin.
Authors: Authors: Domingo A, Yadav R, Shah S, Hendriks WT, Erdin S, Gao D, O'Keefe K, Currall B, Gusella JF, Sharma N, Ozelius LJ, Ehrlich ME, Talkowski ME, Bragg DC.
Am J Hum Genet
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A Multi-omic Huntington's Disease Transgenic Sheep-Model Database for Investigating Disease Pathogenesis.
Authors: Authors: Mears ER, Handley RR, Grant MJ, Reid SJ, Day BT, Rudiger SR, McLaughlan CJ, Verma PJ, Bawden SC, Patassini S, Unwin RD, Cooper GJS, Gusella JF, MacDonald ME, Brauning R, Maclean P, Pearson JF, Waldvogel HJ, Faull RLM, Snell RG.
J Huntingtons Dis
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Huntington's disease: Nearly four decades of human molecular genetics.
Authors: Authors: Gusella JF, Lee JM, MacDonald ME.
Hum Mol Genet
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Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington's Disease.
Authors: Authors: Hong EP, Chao MJ, Massey T, McAllister B, Lobanov S, Jones L, Holmans P, Kwak S, Orth M, Ciosi M, Monckton DG, Long JD, Lucente D, Wheeler VC, MacDonald ME, Gusella JF, Lee JM.
J Huntingtons Dis
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16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro.
Authors: Authors: Sundberg M, Pinson H, Smith RS, Winden KD, Venugopal P, Tai DJC, Gusella JF, Talkowski ME, Walsh CA, Tegmark M, Sahin M.
Nat Commun
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Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease.
Authors: Authors: McAllister B, Gusella JF, Landwehrmeyer GB, Lee JM, MacDonald ME, Orth M, Rosser AE, Williams NM, Holmans P, Jones L, Massey TH.
Neurology
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Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.
Authors: Authors: Jung R, Lee Y, Barker D, Correia K, Shin B, Loupe J, Collins RL, Lucente D, Ruliera J, Gillis T, Mysore JS, Rodan L, Picker J, Lee JM, Howland D, Lee R, Kwak S, MacDonald ME, Gusella JF, Seong IS.
Hum Mol Genet
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CNV profiles of Chinese pediatric patients with developmental disorders.
Authors: Authors: Yuan H, Shangguan S, Li Z, Luo J, Su J, Yao R, Zhang S, Liang C, Chen Q, Gao Z, Zhu Y, Zhang S, Li W, Lu W, Zhang Y, Xie H, Liu F, Wang Q, Lin Y, Liu L, Wang X, Liang L, Zhong J, Li H, Qiu H, Zhang H, Yan M, Mireguli M, Liu Y, Zhang D, Wang H, Lv H, Xie B, Gui C, Cui X, Zou L, Wang J, Gusella JF, Shen Y, Chen X.
Genet Med
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