A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation
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.
|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|
|Publisher Name||PLoS Genetics|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/29117179|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14350|