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

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

6 Scopus citations

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 (US)
Article number	e1007072
Journal	PLoS genetics
Volume	13
Issue number	11
DOIs	https://doi.org/10.1371/journal.pgen.1007072
State	Published - Nov 2017

All Science Journal Classification (ASJC) codes

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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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), [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.

@article{d2ddbec3ed1f434ca0dcdcb075ca3465,

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 = "Funding Information: This work was supported by grants from the Congress Directed Medical Research Program (BC995364 and DAMD17-01-1-0241), Cure Cancer Australia Foundation, NHMRC Australia (projects 1047149, Fellowships 1058356, 481310, 1043400), the Australian Research Council Discovery Project (DP110102288), Princeton University, NIH grant 1R01GM110161-01 (AK), Sidney Kimmel Foundation for Cancer Research (AK), Burroughs Wellcome Foundation (AK), Banque Nationale de Paris-Paribas Australia and New Zealand, Mostyn Family Foundation, Cue Clothing Co., Estee Lauder Australia, RT Hall Trust and Fellowships (ECF-13-08 and ECF-16-022) from the National Breast Cancer Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was made possible by extensive contributions of resources and expertise from the Australian Phenomics Network, including the Australian Phenomics Facility (and in particular Vicki Adams her role in screening), Australian National University Canberra, the Histopathology and Organ Pathology Service at University of Melbourne, the ES-Mouse Service at Monash University Melbourne and the Australian Genome Research Facility Brisbane, all funded in part by MNRF and NCRIS grants. We thank Yoichiro Iwakura from the Institute of Medical Science, University of Tokyo, for the Oas2 constructs, Ms. Gillian Lehrbach for assistance with tissue culture, Anaiis Zaratzian for assistance with histology and the staff of the Garvan Institute animal facilities in Moss Vale and Sydney.",

year = "2017",

month = nov,

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

language = "English (US)",

volume = "13",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "11",

}

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, 11.2017.

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

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 - Funding Information: This work was supported by grants from the Congress Directed Medical Research Program (BC995364 and DAMD17-01-1-0241), Cure Cancer Australia Foundation, NHMRC Australia (projects 1047149, Fellowships 1058356, 481310, 1043400), the Australian Research Council Discovery Project (DP110102288), Princeton University, NIH grant 1R01GM110161-01 (AK), Sidney Kimmel Foundation for Cancer Research (AK), Burroughs Wellcome Foundation (AK), Banque Nationale de Paris-Paribas Australia and New Zealand, Mostyn Family Foundation, Cue Clothing Co., Estee Lauder Australia, RT Hall Trust and Fellowships (ECF-13-08 and ECF-16-022) from the National Breast Cancer Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was made possible by extensive contributions of resources and expertise from the Australian Phenomics Network, including the Australian Phenomics Facility (and in particular Vicki Adams her role in screening), Australian National University Canberra, the Histopathology and Organ Pathology Service at University of Melbourne, the ES-Mouse Service at Monash University Melbourne and the Australian Genome Research Facility Brisbane, all funded in part by MNRF and NCRIS grants. We thank Yoichiro Iwakura from the Institute of Medical Science, University of Tokyo, for the Oas2 constructs, Ms. Gillian Lehrbach for assistance with tissue culture, Anaiis Zaratzian for assistance with histology and the staff of the Garvan Institute animal facilities in Moss Vale and Sydney.

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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DO - 10.1371/journal.pgen.1007072

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