A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

Autor: Oakes SR; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.; St. Vincent's Clinical School, UNSW Medicine, UNSW Sydney, NSW, Australia., Gallego-Ortega D; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.; St. Vincent's Clinical School, UNSW Medicine, UNSW Sydney, NSW, Australia., Stanford PM; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Junankar S; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.; St. Vincent's Clinical School, UNSW Medicine, UNSW Sydney, NSW, Australia., Au WWY; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Kikhtyak Z; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., von Korff A; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Sergio CM; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Law AMK; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Castillo LE; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Allerdice SL; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Young AIJ; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Piggin C; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia., Whittle B; Australian Phenomics Facility, The Australian National University, Canberra, ACT, Australia., Bertram E; Australian Phenomics Facility, The Australian National University, Canberra, ACT, Australia., Naylor MJ; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.; School of Medical Sciences and Bosch Institute, Sydney Medical School, University of Sydney, Sydney, NSW, Australia., Roden DL; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.; St. Vincent's Clinical School, UNSW Medicine, UNSW Sydney, NSW, Australia., Donovan J; Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America., Korennykh A; Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America., Goodnow CC; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.; St. Vincent's Clinical School, UNSW Medicine, UNSW Sydney, NSW, Australia.; Australian Phenomics Facility, The Australian National University, Canberra, ACT, Australia., O'Bryan MK; The School of Biological Sciences, Monash University, Clayton, Australia., Ormandy CJ; Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.; St. Vincent's Clinical School, UNSW Medicine, UNSW Sydney, NSW, Australia.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2017 Nov 08; Vol. 13 (11), pp. e1007072. Date of Electronic Publication: 2017 Nov 08 (Print Publication: 2017).
DOI: 10.1371/journal.pgen.1007072
Abstrakt: We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation.
Databáze: MEDLINE