TY - JOUR
T1 - A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation
AU - Oakes, Samantha R.
AU - Gallego-Ortega, David
AU - Stanford, Prudence M.
AU - Junankar, Simon
AU - Au, Wendy Wing Yee
AU - Kikhtyak, Zoya
AU - von Korff, Anita
AU - Sergio, Claudio M.
AU - Law, Andrew M.K.
AU - Castillo, Lesley E.
AU - Allerdice, Stephanie L.
AU - Young, Adelaide I.J.
AU - Piggin, Catherine
AU - Whittle, Belinda
AU - Bertram, Edward
AU - Naylor, Matthew J.
AU - Roden, Daniel L.
AU - Donovan, Jesse
AU - Korennykh, Alexei
AU - Goodnow, Christopher C.
AU - O’Bryan, Moira K.
AU - Ormandy, Christopher J.
N1 - Publisher Copyright:
© 2017 Oakes et al.
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85036607316
UR - https://www.scopus.com/pages/publications/85036607316#tab=citedBy
U2 - 10.1371/journal.pgen.1007072
DO - 10.1371/journal.pgen.1007072
M3 - Article
C2 - 29117179
AN - SCOPUS:85036607316
SN - 1553-7390
VL - 13
JO - PLoS genetics
JF - PLoS genetics
IS - 11
M1 - e1007072
ER -