Hypomorphic mutation of the mouse Huntingtons disease gene orthologue
Rare individuals with hypomorphic inactivating mutations in the Huntingtons Disease (HD) gene (HTT), identified by CAG repeat expansion in the eponymous neurodegenerative disorder, exhibit variable abnormalities that imply HTT essential roles during organ development. Here we report phenotypes produced when increasingly severe hypomorphic mutations in Htt, the murine HTT orthologue (in HdhneoQ20, HdhneoQ50, HdhneoQ111 mice), were placed over a null allele (Hdhex4/5). The most severe hypomorphic allele failed to rescue null lethality at gastrulation, while the intermediate alleles yielded perinatal lethality and a variety of fetal abnormalities affecting body size, skin, skeletal and ear formation, and transient defects in hematopoiesis. Comparative molecular analysis of wild-type and Htt-null retinoic acid-differentiated cells revealed gene network dysregulation associated with organ development and proposed polycomb repressive complexes and miRNAs as molecular mediators. Together these findings demonstrate that the HD gene acts both pre- and post-gastrulation and possibly suggest pleiotropic consequences of HTT-lowering therapeutic strategies.\n\nAuthor SummaryThe HTT gene product mutated in Huntingtons Disease (HD) has essential roles during normal organism development, however, still not fully predictable are the functional consequences of its partial inactivation. Our genetic study provides a comprehensive effects description of progressively stronger suppression of Htt gene, the murine HTT counterpart. The most severe Htt reduction leads to embryo lethality, while intermediate Htt dosages yield a variety of developmental abnormalities affecting body size, skin, skeletal and ear formation, and hematopoiesis. Complementing molecular analysis in differentiating cells depleted of a functional Htt gene further elucidates genes networks dysregulated during organ development and proposes chromatin regulators and short non-coding RNAs as key molecular mediators. Together these findings demonstrate that the HD gene acts both at early and later stages of development, thus possibly suggesting long-term consequences associated to the newest HD therapeutic strategies aimed at lowering the HTT gene product.