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

Samantha R. Oakes, David Gallego-Ortega, Prudence M. Stanford, Simon Junankar, Wendy Wing Yee Au, Zoya Kikhtyak, Anita von Korff, Claudio M. Sergio, Andrew M.K. Law, Lesley E. Castillo, Stephanie L. Allerdice, Adelaide I.J. Young, Catherine Piggin, Belinda Whittle, Edward Bertram, Matthew J. Naylor, Daniel L. Roden, Jesse Donovan, Alexei Korennykh, Christopher C. GoodnowMoira K. O’Bryan, Christopher J. Ormandy

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere1007072
JournalPLoS genetics
Volume13
Issue number11
DOIs
StatePublished - Nov 2017

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Oakes, S. R., Gallego-Ortega, D., Stanford, P. M., Junankar, S., Au, W. W. Y., Kikhtyak, Z., von Korff, A., Sergio, C. M., Law, A. M. K., Castillo, L. E., Allerdice, S. L., Young, A. I. J., Piggin, C., Whittle, B., Bertram, E., Naylor, M. J., Roden, D. L., Donovan, J., Korennykh, A., ... Ormandy, C. J. (2017). A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation. PLoS genetics, 13(11), [e1007072]. https://doi.org/10.1371/journal.pgen.1007072