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 & 2 others Moira K. O’Bryan, Christopher J. Ormandy

Research output: Contribution to journalArticleResearchpeer-review

3 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 languageEnglish
Article numbere1007072
Number of pages24
JournalPLoS Genetics
Volume13
Issue number11
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • ribonucleases
  • mammary glands
  • lactation
  • gene expression
  • milk
  • small interfering RNAs
  • mastitis
  • epithelial cells

Cite this

Oakes, S. R., Gallego-Ortega, D., Stanford, P. M., Junankar, S., Au, W. W. Y., Kikhtyak, Z., ... Ormandy, C. J. (2017). A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation. PLoS Genetics, 13(11), [e1007072]. https://doi.org/10.1371/journal.pgen.1007072
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. / A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation. In: PLoS Genetics. 2017 ; Vol. 13, No. 11.
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title = "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.",
keywords = "ribonucleases, mammary glands, lactation, gene expression, milk, small interfering RNAs, mastitis, epithelial cells",
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’Bryan, {Moira K.} and Ormandy, {Christopher J.}",
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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

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

In: PLoS Genetics, Vol. 13, No. 11, e1007072, 01.11.2017.

Research output: Contribution to journalArticleResearchpeer-review

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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 - 2017/11/1

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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.

KW - ribonucleases

KW - mammary glands

KW - lactation

KW - gene expression

KW - milk

KW - small interfering RNAs

KW - mastitis

KW - epithelial cells

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DO - 10.1371/journal.pgen.1007072

M3 - Article

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JO - PLoS Genetics

JF - PLoS Genetics

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Oakes SR, Gallego-Ortega D, Stanford PM, Junankar S, Au WWY, Kikhtyak Z et al. A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation. PLoS Genetics. 2017 Nov 1;13(11). e1007072. https://doi.org/10.1371/journal.pgen.1007072