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Chromosome substitution strain assessment of a Huntington's disease modifier locus.

Ramos EM, Kovalenko M, Guide JR, St Claire J, Gillis T, Mysore JS, Sequeiros J, Wheeler VC, Alonso I, MacDonald ME - Mamm. Genome (2015)

Bottom Line: Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes.These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains.This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA, esilvaramos@mgh.harvard.edu.

ABSTRACT
Huntington's disease (HD) is a dominant neurodegenerative disorder that is due to expansion of an unstable HTT CAG repeat for which genome-wide genetic scans are now revealing chromosome regions that contain disease-modifying genes. We have explored a novel human-mouse cross-species functional prioritisation approach, by evaluating the HD modifier 6q23-24 linkage interval. This unbiased strategy employs C57BL/6J (B6J) Hdh(Q111) knock-in mice, replicates of the HD mutation, and the C57BL/6J-chr10(A/J)/NaJ chromosome substitution strain (CSS10), in which only chromosome 10 (chr10), in synteny with the human 6q23-24 region, is derived from the A/J (AJ) strain. Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes. Testing of F1 progeny confirmed that a single AJ chromosome had a significant effect on the rate of body weight gain and in Hdh(Q111) mice the AJ chromosome was associated subtle alterations in somatic CAG instability in the liver and the formation of intra-nuclear inclusions, as well as DARPP-32 levels, in the striatum. These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains. This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

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CAG repeat size of the knock-in alleles in HdhQ111/+B6J and HdhQ111/+B6J.AJ10 progeny. The mean CAG repeat size of the mice used in this study was 142.0 ± 3.2 for HdhQ111/+B6J (n = 27) and 141.3 ± 2.8 for HdhQ111/+B6J.AJ10 (n = 28). Solid line represents mean of CAG repeat for each genotype while the dashed line represents the CAG repeat size transmitted from the parental HdhQ111/+B6J mice (139 CAGs)
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Fig4: CAG repeat size of the knock-in alleles in HdhQ111/+B6J and HdhQ111/+B6J.AJ10 progeny. The mean CAG repeat size of the mice used in this study was 142.0 ± 3.2 for HdhQ111/+B6J (n = 27) and 141.3 ± 2.8 for HdhQ111/+B6J.AJ10 (n = 28). Solid line represents mean of CAG repeat for each genotype while the dashed line represents the CAG repeat size transmitted from the parental HdhQ111/+B6J mice (139 CAGs)

Mentions: Previous studies have shown that in HdhQ111 knock-in mice intergenerational CAG repeat length changes with a paternal expansion bias (Lloret et al. 2006; Wheeler et al. 1999). In our study, the Htt mutant allele was transmitted from male HdhQ111/+ knock-in mice with the same background (B6J) and constitutional (i.e. in tail DNA) CAG repeat length (139 CAG repeats). Therefore, as expected, we observed a paternal expansion bias (74 % in crosses of HdhQ111/+ mice with B6J and 82 % in crosses with CSS10 mice), but no significant repeat length difference in the transmissions of the Htt 139 CAG allele to HdhQ111/+B6J (mean ± SD = 3.04 ± 3.18) and HdhQ111/+B6J.AJ10 mice (mean ± SD = 2.25 ± 2.77) was detected. Figure 4 shows the actual CAG repeat size of the HdhQ111 knock-in allele in both HdhQ111/+B6J and HdhQ111/+B6J.AJ10 progeny used in this study.Fig. 4


Chromosome substitution strain assessment of a Huntington's disease modifier locus.

Ramos EM, Kovalenko M, Guide JR, St Claire J, Gillis T, Mysore JS, Sequeiros J, Wheeler VC, Alonso I, MacDonald ME - Mamm. Genome (2015)

CAG repeat size of the knock-in alleles in HdhQ111/+B6J and HdhQ111/+B6J.AJ10 progeny. The mean CAG repeat size of the mice used in this study was 142.0 ± 3.2 for HdhQ111/+B6J (n = 27) and 141.3 ± 2.8 for HdhQ111/+B6J.AJ10 (n = 28). Solid line represents mean of CAG repeat for each genotype while the dashed line represents the CAG repeat size transmitted from the parental HdhQ111/+B6J mice (139 CAGs)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4372682&req=5

Fig4: CAG repeat size of the knock-in alleles in HdhQ111/+B6J and HdhQ111/+B6J.AJ10 progeny. The mean CAG repeat size of the mice used in this study was 142.0 ± 3.2 for HdhQ111/+B6J (n = 27) and 141.3 ± 2.8 for HdhQ111/+B6J.AJ10 (n = 28). Solid line represents mean of CAG repeat for each genotype while the dashed line represents the CAG repeat size transmitted from the parental HdhQ111/+B6J mice (139 CAGs)
Mentions: Previous studies have shown that in HdhQ111 knock-in mice intergenerational CAG repeat length changes with a paternal expansion bias (Lloret et al. 2006; Wheeler et al. 1999). In our study, the Htt mutant allele was transmitted from male HdhQ111/+ knock-in mice with the same background (B6J) and constitutional (i.e. in tail DNA) CAG repeat length (139 CAG repeats). Therefore, as expected, we observed a paternal expansion bias (74 % in crosses of HdhQ111/+ mice with B6J and 82 % in crosses with CSS10 mice), but no significant repeat length difference in the transmissions of the Htt 139 CAG allele to HdhQ111/+B6J (mean ± SD = 3.04 ± 3.18) and HdhQ111/+B6J.AJ10 mice (mean ± SD = 2.25 ± 2.77) was detected. Figure 4 shows the actual CAG repeat size of the HdhQ111 knock-in allele in both HdhQ111/+B6J and HdhQ111/+B6J.AJ10 progeny used in this study.Fig. 4

Bottom Line: Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes.These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains.This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA, esilvaramos@mgh.harvard.edu.

ABSTRACT
Huntington's disease (HD) is a dominant neurodegenerative disorder that is due to expansion of an unstable HTT CAG repeat for which genome-wide genetic scans are now revealing chromosome regions that contain disease-modifying genes. We have explored a novel human-mouse cross-species functional prioritisation approach, by evaluating the HD modifier 6q23-24 linkage interval. This unbiased strategy employs C57BL/6J (B6J) Hdh(Q111) knock-in mice, replicates of the HD mutation, and the C57BL/6J-chr10(A/J)/NaJ chromosome substitution strain (CSS10), in which only chromosome 10 (chr10), in synteny with the human 6q23-24 region, is derived from the A/J (AJ) strain. Crosses were performed to assess the possibility of dominantly acting chr10 AJ-B6J variants of strong effect that may modulate CAG-dependent Hdh(Q111/+) phenotypes. Testing of F1 progeny confirmed that a single AJ chromosome had a significant effect on the rate of body weight gain and in Hdh(Q111) mice the AJ chromosome was associated subtle alterations in somatic CAG instability in the liver and the formation of intra-nuclear inclusions, as well as DARPP-32 levels, in the striatum. These findings in relatively small cohorts are suggestive of dominant chr10 AJ-B6 variants that may modify effects of the CAG expansion, and encourage a larger study with CSS10 and sub-strains. This cross-species approach may therefore be suited to functional in vivo prioritisation of genomic regions harbouring genes that can modify the early effects of the HD mutation.

Show MeSH
Related in: MedlinePlus