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

Samantha Oakes ,Alexei Korennykh,Simon Junankar,Jesse Donovan,Matthew J Naylor,Christopher J Ormandy,Anita Von Korff,Belinda Whittle,Stephanie L Allerdice,Zoya Kikhtyak,Andrew M K Law,Christopher C Goodnow,David Gallego‐Ortega ,Moira K O’bryan ,Lesley Castillo ,Wendy W.y Au ,Daniel Roden ,Prudence M Stanford,Catherine Piggin,C Marcelo Sergio ,Edward M Bertram ,Alex Young

doi:10.1371/journal.pgen.1007072

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.

Highlights

The oligoadenylate synthetase (OAS) enzymes are activated by detection of double stranded RNA produced during the viral life cycle, and in response polymerize ATP into 2 ́-5 ́ linked oligoadenylates (2-5A) of various lengths
Using ENU-mutagenesis in mice we discovered a pedigree with lactation failure
Mammary development through puberty and pregnancy appeared normal in mutant animals, but the activation of lactation failed in the immediate post partum period and no milk reached the pups

Summary

Introduction

The oligoadenylate synthetase (OAS) enzymes are activated by detection of double stranded RNA produced during the viral life cycle, and in response polymerize ATP into 2 ́-5 ́ linked oligoadenylates (2-5A) of various lengths. Mechanistic detail is lacking, it is proposed that OAS enzymes can activate anti viral responses via mechanisms independently of 2-5A production, by direct interactions within the viral signaling complex. This complex is tethered to the mitochondrial outer membrane by the scaffold protein MAVS, and contains RIG-I, related helicase MDA5, and possibly OAS family members [5]. We report a mutation of OAS2 that produces lactation failure in an otherwise normal mouse This is the first demonstration that a viral recognition pathway can regulate lactation

Methods

Results

Discussion

Conclusion