Fly-half Owen Farrell has been ruled out of England's entire Six Nations campaign after suffering knee ligament damage.
The 23-year-old went off during Saracens' European Champions Cup defeat to Clermont over the weekend and will not recover in time to remain in Stuart Lancaster's squad.
Farrell becomes the latest player to be ruled out of the tournament after injuries to Joe Launchbury, Ben Morgan and Ben Foden.
"It's a real shame for Owen that he sustained this injury and we wish him the best for his recovery," Lancaster said.
"We are fortunate to have three other No 10s in the squad in what is a very competitive position and we will look forward to seeing how they go over the RBS 6 Nations. We will continue to assess and treat the other players' injuries and will provide an update at the launch tomorrow."
Other injury victims from the weekend's fixtures include Geoff Parling, Brad Barritt, Tom Wood, and Kyle Eastmond, with the quartet all being monitored.
England face Wales in their opening Six Nations match at the Millennium Stadium on 6 February.