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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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One single copy of AJ chr10 has an effect on the patterns of weight gain. Scatter plots represent the individual values of the initial weight (at ~3 weeks of age), the final weight (at ~24 weeks of age) and the mean weight gain per day for a female and b male mice. The mice used for the body weight analysis are as follows: Hdh+/+B6J (13 females and 14 males), HdhQ111/+B6J (9 females and 16 males), Hdh+/+B6J.AJ10 (10 females and 10 males) and HdhQ111/+B6J.AJ10 (15 females and 5 males). Line represents mean of values for each genotype. ****p < 0.0001, ***p < 0.001, **p < 0.01 and *p < 0.05
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Fig3: One single copy of AJ chr10 has an effect on the patterns of weight gain. Scatter plots represent the individual values of the initial weight (at ~3 weeks of age), the final weight (at ~24 weeks of age) and the mean weight gain per day for a female and b male mice. The mice used for the body weight analysis are as follows: Hdh+/+B6J (13 females and 14 males), HdhQ111/+B6J (9 females and 16 males), Hdh+/+B6J.AJ10 (10 females and 10 males) and HdhQ111/+B6J.AJ10 (15 females and 5 males). Line represents mean of values for each genotype. ****p < 0.0001, ***p < 0.001, **p < 0.01 and *p < 0.05

Mentions: We examined the rate of body weight gain as a primary endpoint because it has been reported, from phenotyping across the members of the entire CSS panel, that dominant AJ chr10 variants dampen the rapid rate of body weight gain of B6J mice, in F1 B6J.AJ10 mice (Burrage et al. 2010). Furthermore, in HD subjects weight loss is often observed in the course of the disease (Aziz et al. 2008; Djousse et al. 2002; Farrer and Yu 1985; Robbins et al. 2006; Sanberg et al. 1981) despite normal to very high caloric intake (Marder et al. 2009; Morales et al. 1989; Trejo et al. 2004). It is correlated with disease progression (Myers et al. 1991) and patients with higher expanded CAG repeat exhibit more rapid loss of body weight (Aziz et al. 2008). In the knock-in HdhQ111 mice (on a CD1 background), homozygous males had a lower body weight than wild type and heterozygous mice at 28 weeks (Menalled et al. 2009). Therefore, to assess the potential effect of the HdhQ111 mutation on a B6J background and of the different test genetic backgrounds (chr10B6J/B6J vs chr10B6J/AJ), we analyzed body weight at three different ages (3, 14, and 24 weeks). As shown in Fig. 3, wild type B6J mice showed significant lower body weight than wild type B6J.AJ10 mice at 3 weeks of age for both genders (p = 0.0008, mean IW ± SD: 10.02 ± 1.89 vs 13.03 ± 1.74 for females and p < 0.0001, mean IW ± SD: 9.22 ± 1.72 vs 13.92 ± 2.29 for males). However, they tended to gain more weight per day than B6J.AJ10 mice (p = 0.0026, mean WG ± SD: 0.081 ± 0.013 vs 0.063 ± 0.012 for females and p = 0.0302, WG ± SD: 0.133 ± 0.014 vs 0.113 ± 0.024 for males), resulting in similar body weights between B6J and B6J.AJ10 mice by week 24 (mean FW ± SD: 21.64 ± 1.35 vs 21.99 ± 0.64 for females, and 28.35 ± 1.63 vs 30.13 ± 2.03 in males, respectively). Therefore, the presence of the AJ10 chromosome was associated with less rapid weight gain, thereby confirming an earlier phenotypic effect on an otherwise B6J background. However, there was no significant difference in weight at any time point between HdhQ111 mutant and wild type mice, for either of the two different chr10 genetic backgrounds.Fig. 3


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)

One single copy of AJ chr10 has an effect on the patterns of weight gain. Scatter plots represent the individual values of the initial weight (at ~3 weeks of age), the final weight (at ~24 weeks of age) and the mean weight gain per day for a female and b male mice. The mice used for the body weight analysis are as follows: Hdh+/+B6J (13 females and 14 males), HdhQ111/+B6J (9 females and 16 males), Hdh+/+B6J.AJ10 (10 females and 10 males) and HdhQ111/+B6J.AJ10 (15 females and 5 males). Line represents mean of values for each genotype. ****p < 0.0001, ***p < 0.001, **p < 0.01 and *p < 0.05
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig3: One single copy of AJ chr10 has an effect on the patterns of weight gain. Scatter plots represent the individual values of the initial weight (at ~3 weeks of age), the final weight (at ~24 weeks of age) and the mean weight gain per day for a female and b male mice. The mice used for the body weight analysis are as follows: Hdh+/+B6J (13 females and 14 males), HdhQ111/+B6J (9 females and 16 males), Hdh+/+B6J.AJ10 (10 females and 10 males) and HdhQ111/+B6J.AJ10 (15 females and 5 males). Line represents mean of values for each genotype. ****p < 0.0001, ***p < 0.001, **p < 0.01 and *p < 0.05
Mentions: We examined the rate of body weight gain as a primary endpoint because it has been reported, from phenotyping across the members of the entire CSS panel, that dominant AJ chr10 variants dampen the rapid rate of body weight gain of B6J mice, in F1 B6J.AJ10 mice (Burrage et al. 2010). Furthermore, in HD subjects weight loss is often observed in the course of the disease (Aziz et al. 2008; Djousse et al. 2002; Farrer and Yu 1985; Robbins et al. 2006; Sanberg et al. 1981) despite normal to very high caloric intake (Marder et al. 2009; Morales et al. 1989; Trejo et al. 2004). It is correlated with disease progression (Myers et al. 1991) and patients with higher expanded CAG repeat exhibit more rapid loss of body weight (Aziz et al. 2008). In the knock-in HdhQ111 mice (on a CD1 background), homozygous males had a lower body weight than wild type and heterozygous mice at 28 weeks (Menalled et al. 2009). Therefore, to assess the potential effect of the HdhQ111 mutation on a B6J background and of the different test genetic backgrounds (chr10B6J/B6J vs chr10B6J/AJ), we analyzed body weight at three different ages (3, 14, and 24 weeks). As shown in Fig. 3, wild type B6J mice showed significant lower body weight than wild type B6J.AJ10 mice at 3 weeks of age for both genders (p = 0.0008, mean IW ± SD: 10.02 ± 1.89 vs 13.03 ± 1.74 for females and p < 0.0001, mean IW ± SD: 9.22 ± 1.72 vs 13.92 ± 2.29 for males). However, they tended to gain more weight per day than B6J.AJ10 mice (p = 0.0026, mean WG ± SD: 0.081 ± 0.013 vs 0.063 ± 0.012 for females and p = 0.0302, WG ± SD: 0.133 ± 0.014 vs 0.113 ± 0.024 for males), resulting in similar body weights between B6J and B6J.AJ10 mice by week 24 (mean FW ± SD: 21.64 ± 1.35 vs 21.99 ± 0.64 for females, and 28.35 ± 1.63 vs 30.13 ± 2.03 in males, respectively). Therefore, the presence of the AJ10 chromosome was associated with less rapid weight gain, thereby confirming an earlier phenotypic effect on an otherwise B6J background. However, there was no significant difference in weight at any time point between HdhQ111 mutant and wild type mice, for either of the two different chr10 genetic backgrounds.Fig. 3

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