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

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.

Type Journal
ISBN 1553-7404 (Electronic) 1553-7390 (Linking)
Authors 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.; Goodnow, C. C.; O'Bryan, M. K.; Ormandy, C. J.
Responsible Garvan Author Prof Chris Ormandy
Publisher Name PLoS Genetics
Published Date 2017-11-08 00:00:00
Published Volume 13
Published Issue 11
Published Pages e1007072
Status Published in-print
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/29117179