Poster Presentation 30th Lorne Cancer Conference 2018

A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation (#233)

Samantha R Oakes 1 2 , David Gallego Ortega 1 2 , Prudence M Stanford 1 , Simon Junankar 1 2 , Wendy WY Au 1 , Zoya Kikhtyak 1 , Anita von Korff 1 , Claudio M Sergio 1 , Andrew MK Law 1 , Lesley E Castillo 1 , Stephanie L Allerdice 1 , Adelaide IJ Young 1 , Catherine Piggin 1 , Belinda Whittle 3 , Edward Bertram 3 , Matthew J Naylor 4 , Daniel L Roden 1 , Jesse Donovan 5 , Alexei Korennykh 5 , Christopher C Goodnow 1 2 3 , Moira K O'Bryan 6 , Christopher J Ormandy 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St. Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW, Australia
  3. Australian Phenomics Facility, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
  4. Physiology, School of Medical Sciences, Sydney University, Sydney, NSW, Australia
  5. Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA
  6. The School of Biological Sciences, Monash University, Clayton, VIC, Australia

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.