A recessive mutation in Rhbdf2 is associated with reduced TLR-induced TNFα secretion. (A) Phenotype of the index sinecure mouse. Peritoneal macrophages from 62 G3 descendants of ENU-mutagenized sires were stimulated with a panel of TLR ligands, and TNFα production measured by L-929 bioassay. Genome-wide (B) and fine (C) mapping of the sinecure mutation to distal chromosome 11. (D) A homozygous transversion mutation in Rhbdf2, corresponding to an isoleucine to phenylalanine missense mutation (E) in the N-terminal transmembrane domain (TM) of iRhom2 protein. Predicted phosphorylation (P) and glycosylation sites are also indicated. (F) Topology of the iRhom2 protein, indicating the position of the sinecure missense mutation.