Hypomorphic mutation of the mouse Huntington's disease gene orthologue

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Differentiation / genetics
  • Disease Models, Animal
  • Gene Frequency / genetics
  • Genotype
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / physiology
  • Huntington Disease / genetics*
  • Mice / embryology
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Phenotype


  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins