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PLoS Genet. 2019 Mar 21;15(3):e1007765. doi: 10.1371/journal.pgen.1007765. eCollection 2019 Mar.

Hypomorphic mutation of the mouse Huntington's disease gene orthologue.

Author information

1
Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States of America.
2
Laboratory of Translational Genomics, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
3
Cutaneous Biology Research Center (CBRC), Mass General Hospital, Harvard Medical School, Charlestown, MA, United States of America.
4
Frederick Community College, Frederick MD, United States of America.
5
NeuroEpigenetics Laboratory, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
6
Broad Institute of Harvard and MIT, Cambridge, MA, United States of America.
7
Department of Neurology, Harvard Medical School, Boston, MA, United States of America.
8
Department of Genetics, Harvard Medical School, Boston, MA, United States of America.

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.

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