Human Molecular Genetics Advance Access published online on May 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl125
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1 Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston MA 02114, USA
* To whom correspondence should be addressed. Genetically precise models of Huntington's disease (HD), Hdh CAG knock-in mice, are powerful systems in which to study phenotypes associated with expanded HD CAG repeats. To dissect the genetic pathways that underlie such phenotypes we have generated HdhQ111 knock-in mouse lines that are congenic for C57BL/6, FVB/N and 129Sv inbred genetic backgrounds and investigated four HdhQ111 phenotypes in these three genetic backgrounds: the intergenerational instability of the HD CAG repeat, and the striatal-specific somatic HD CAG repeat expansion, nuclear mutant huntingtin accumulation and intranuclear inclusion formation. Our results reveal increased intergenerational and somatic instability of the HD CAG repeat in C57BL/6 and FVB/N backgrounds compared to the 129Sv background. The accumulation of nuclear mutant huntingtin and the formation of intranuclear inclusions were fastest in the C57BL/6 background, slowest in the 129Sv background and intermediate in the FVB/N background. Inbred strain-specific differences were independent of constitutive HD CAG repeat size and did not correlate with Hdh mRNA levels. These data provide evidence for genetic modifiers of both intergenerational HD CAG repeat instability and striatal-specific phenotypes. Different relative contributions of C57BL/6 and 129Sv genetic backgrounds to the onset of nuclear mutant huntingtin and somatic HD CAG repeat expansion predicts that the initiation of each of these two phenotypes is modified by different genes. Our findings set the stage for defining disease-related genetic pathways that will ultimately provide insight into disease mechanism.
Received March 28, 2006
Revised May 6, 2006
Accepted May 6, 2006
Article
Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice
Alejandro Lloret 1,
Ella Dragileva 1,
Allison Teed 1,
Janice Espinola 1,
Elisa Fossale 1,
Tammy Gillis 1,
Edith Lopez 1,
Richard H. Myers 2,
Marcy E. MacDonald 1,
and
Vanessa C Wheeler 1 *
2 Department of Neurology, Boston University School of Medicine, Boston MA 02118, USA
Vanessa C Wheeler, E-mail: wheeler{at}helix.mgh.harvard.edu
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