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

School of Biological Sciences

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

15 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
Number of pages	24
Journal	PLoS Genetics
Volume	13
Issue number	11
DOIs	https://doi.org/10.1371/journal.pgen.1007072
Publication status	Published - 1 Nov 2017

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1007072

243038718-oaFinal published version, 8.18 MB

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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{c08bf4f679ca409aa6947d0b0cd09e92,

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.",

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{\textquoteright}Bryan, \{Moira K.\} and Ormandy, \{Christopher J.\}",

year = "2017",

month = nov,

day = "1",

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

language = "English",

volume = "13",

journal = "PLoS Genetics",

issn = "1553-7390",

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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

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.

PY - 2017/11/1

Y1 - 2017/11/1

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

UR - https://www.scopus.com/pages/publications/85036607316

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 -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

GGN as a regulator of DNA double strand break repair and genome integrity

NHMRC Research Fellowship

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

GGN as a regulator of DNA double strand break repair and genome integrity

NHMRC Research Fellowship

Cite this