title: Chromosome substitution strain assessment of a Huntington's disease modifier locus.
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.
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA, esilvaramos@mgh.harvard.edu.
authors: Eliana Marisa
authors: EM
authors: Ramos
authors: Marina
authors: M
authors: Kovalenko
authors: Jolene R
authors: JR
authors: Guide
authors: Jason
authors: J
authors: St Claire
authors: Tammy
authors: T
authors: Gillis
authors: Jayalakshmi S
authors: JS
authors: Mysore
authors: Jorge
authors: J
authors: Sequeiros
authors: Vanessa C
authors: VC
authors: Wheeler
authors: Isabel
authors: I
authors: Alonso
authors: Marcy E
authors: ME
authors: MacDonald
mesh_terms: D000483:Alleles; D000818:Animals; D001835:Body Weight; D002877:Chromosomes, Human; D033481:Chromosomes, Mammalian; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism; D005260:Female; D055879:Gene Knock-In Techniques; D014644:Genetic Variation; D042822:Genomic Instability; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D040641:Quantitative Trait Loci; D018911:Trinucleotide Repeats
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
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