Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice.

Full Abstract

Genetically precise models of Huntington's disease (HD), Hdh CAG knock-in mice, are powerful systems in which phenotypes associated with expanded HD CAG repeats are studied. To dissect the genetic pathways that underlie such phenotypes, we have generated Hdh(Q111) knock-in mouse lines that are congenic for C57BL/6, FVB/N and 129Sv inbred genetic backgrounds and investigated four Hdh(Q111) 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 with 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 predict 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.

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Author information

Author/s: Lloret, Alejandro (A); Dragileva, Ella (E); Teed, Allison (A); Espinola, Janice (J); Fossale, Elisa (E); Gillis, Tammy (T); Lopez, Edith (E); Myers, Richard H (RH); MacDonald, Marcy E (ME); Wheeler, Vanessa C (VC);

Affiliation: Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.

Grants: NS032765 (Agency:NINDS NIH HHS) ; NS049206 (Agency:NINDS NIH HHS) ; P50NS016367 (Agency:NINDS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Human molecular genetics (Hum Mol Genet), published in England. (Language: eng)

Reference: 2006-Jun; vol 15 (issue 12) : pp 2015-24

Dates: Created 2006/05/29; Completed 2006/08/10; Revised 2007/11/14;

PMID: 16687439, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Cell Nucleus - metabolism
Corpus Striatum - metabolism; pathology
DNA Repeat Expansion
Female
Huntington Disease - genetics; metabolism; pathology
Intranuclear Inclusion Bodies - metabolism; ultrastructure
Male

Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mutation
Nerve Tissue Proteins - genetics; metabolism
Neurons - metabolism; ultrastructure
Nuclear Proteins - genetics; metabolism
Trinucleotide Repeats

Associated Chemicals: Huntington protein, mouse (0) ; Nerve Tissue Proteins (0) ; Nuclear Proteins (0)

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