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

• Published in: PLoS genetics Vol. 13; no. 11; p. e1007072
• Main Authors: Oakes, Samantha R, Gallego-Ortega, David, Stanford, Prudence M, Junankar, Simon, Au, Wendy Wing Yee, Kikhtyak, Zoya, von Korff, Anita, Sergio, Claudio M, Law, Andrew M K, Castillo, Lesley E, Allerdice, Stephanie L, Young, Adelaide I J, Piggin, Catherine, Whittle, Belinda, Bertram, Edward, Naylor, Matthew J, Roden, Daniel L, Donovan, Jesse, Korennykh, Alexei, Goodnow, Christopher C, O'Bryan, Moira K, Ormandy, Christopher J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.11.2017; Public Library of Science (PLoS)
• Subjects: 2',5'-Oligoadenylate Synthetase - genetics; 2',5'-Oligoadenylate Synthetase - metabolism; Adenine Nucleotides - metabolism; Animals; Biology and life sciences; Cell Culture Techniques; Endoribonucleases - metabolism; Female; Genetic aspects; Humans; Lactation; Lactation - genetics; Mammary glands; Mammary Glands, Animal - metabolism; Medicine and Health Sciences; Mice; Milk; Mutation - genetics; Oligoribonucleotides - metabolism; Physiological aspects; RNA; RNA, Double-Stranded - metabolism; Signal Transduction - genetics
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1007072

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.