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 preand post-gastrulation to support normal development.

Hypomorphic mutation of the mouse huntington’s disease gene orthologue / Murthy, V.; Tebaldi, T.; Yoshida, T.; Erdin, S.; Calzonetti, T.; Vijayvargia, R.; Tripathi, T.; Kerschbamer, E.; Seong, I. S.; Quattrone, A.; Talkowski, M. E.; Gusella, J. F.; Georgopoulos, K.; Macdonald, M. E.; Biagioli, M.. - In: PLOS GENETICS. - ISSN 1553-7390. - 15:3(2019), pp. e100776501-e100776528. [10.1371/journal.pgen.1007765]

Hypomorphic mutation of the mouse huntington’s disease gene orthologue

Tebaldi T.;Tripathi T.;Kerschbamer E.;Quattrone A.;Biagioli M.
2019

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 preand post-gastrulation to support normal development.
3
Murthy, V.; Tebaldi, T.; Yoshida, T.; Erdin, S.; Calzonetti, T.; Vijayvargia, R.; Tripathi, T.; Kerschbamer, E.; Seong, I. S.; Quattrone, A.; Talkowski, M. E.; Gusella, J. F.; Georgopoulos, K.; Macdonald, M. E.; Biagioli, M.
Hypomorphic mutation of the mouse huntington’s disease gene orthologue / Murthy, V.; Tebaldi, T.; Yoshida, T.; Erdin, S.; Calzonetti, T.; Vijayvargia, R.; Tripathi, T.; Kerschbamer, E.; Seong, I. S.; Quattrone, A.; Talkowski, M. E.; Gusella, J. F.; Georgopoulos, K.; Macdonald, M. E.; Biagioli, M.. - In: PLOS GENETICS. - ISSN 1553-7390. - 15:3(2019), pp. e100776501-e100776528. [10.1371/journal.pgen.1007765]
File in questo prodotto:
File Dimensione Formato  
pgen.1007765.pdf

accesso aperto

Tipologia: Versione editoriale (Publisher’s layout)
Licenza: Creative commons
Dimensione 4.92 MB
Formato Adobe PDF
4.92 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11572/288699
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 7
social impact