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. Goodnow; Moira K. O’Bryan; Christopher J. Ormandy

doi:10.1371/journal.pgen.1007072

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

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 language	English
Article number	e1007072
Journal	PLoS Genetics
Volume	13
Issue number	11
DOIs	https://doi.org/10.1371/journal.pgen.1007072
Publication status	Published - Nov 2017

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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), Article e1007072. https://doi.org/10.1371/journal.pgen.1007072

@article{2f7f024857284117b2f9785dbd13fbe5,

title = "A mutation in the viral sensor 2{\textquoteright}-5{\textquoteright}-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.",

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

note = "Publisher Copyright: {\textcopyright} 2017 Oakes et al.",

year = "2017",

month = nov,

doi = "10.1371/journal.pgen.1007072",

language = "English",

volume = "13",

journal = "PLoS Genetics",

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Oakes, SR, Gallego-Ortega, D, Stanford, PM, Junankar, S, Au, WWY, Kikhtyak, Z, von Korff, A, Sergio, CM, Law, AMK, Castillo, LE, Allerdice, SL, Young, AIJ, Piggin, C, Whittle, B, Bertram, E, Naylor, MJ, Roden, DL, Donovan, J, Korennykh, A, Goodnow, CC, O’Bryan, MK & Ormandy, CJ 2017, 'A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation', PLoS Genetics, vol. 13, no. 11, e1007072. https://doi.org/10.1371/journal.pgen.1007072

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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.

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.

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U2 - 10.1371/journal.pgen.1007072

DO - 10.1371/journal.pgen.1007072

M3 - Article

SN - 1553-7390

VL - 13

JO - PLoS Genetics

JF - PLoS Genetics

IS - 11

M1 - e1007072

ER -

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

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