Murthy, V;
Tebaldi, T;
Yoshida, T;
Erdin, S;
Calzonetti, T;
Vijayvargia, R;
Tripathi, T;
... Biagioli, M; + view all
(2019)
Hypomorphic mutation of the mouse Huntington's disease gene orthologue.
PLOS Genetics
, 15
(3)
, Article e1007765. 10.1371/journal.pgen.1007765.
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Abstract
Rare individuals with inactivating mutations in the Huntington’s disease gene (HTT) exhibit variable abnormalities that imply essential HTT roles during organ development. Here we report phenotypes produced when increasingly severe hypomorphic mutations in the murine HTT orthologue Htt, (HdhneoQ20, HdhneoQ50, HdhneoQ111), were placed over a null allele (Hdhex4/5). The most severe hypomorphic allele failed to rescue null lethality at gastrulation, while the intermediate, though still severe, alleles yielded recessive 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 that nominate polycomb repressive complexes and miRNAs as molecular mediators. Together these findings demonstrate that Htt is required both pre- and post-gastrulation to support normal development.
| Type: | Article |
|---|---|
| Title: | Hypomorphic mutation of the mouse Huntington's disease gene orthologue |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1007765 |
| Publisher version: | https://doi.org/10.1371/journal.pgen.1007765 |
| Language: | English |
| Additional information: | Copyright © 2019 Murthy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| Keywords: | Embryos, MicroRNAs, Gene expression, Alleles, Cell differentiation, Ears, Hematopoiesis, Mutation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10074083 |
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