IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database

IFN-gamma signaling is essential for the innate immune defense againstmycobacterial infections. IFN-gamma signals through the IFN-gamma receptor, which consists of a tetramer of two IFN-gamma R1 chains in complex with two IFN-gamma R2 chains, where IFN-gamma R1 is the ligand-binding chain of the interferon-gamma receptor and IFN-gamma R2 is the signal-transducing chain of the IFN-gamma receptor. Germline mutations in the gene IFNGR1 encoding the IFN-gamma R1 cause a primary immunodeficiency that mainly leads tomycobacterial infections. Here, we review the molecular basis of this immunodeficiency in the 130 individuals described to date, and report mutations in five new individuals, bringing the total number to 135 individuals from 98 kindreds. Forty unique IFNGR1 mutations have been reported and they exert either an autosomal dominant or an autosomal recessive effect. Mutations resulting in premature stopcodons represent the majority of IFNGR1 mutations (60%; 24 out of 40), followed by amino acid substitutions (28%, 11 out of 40). All known mutations, as well as 287 other variations, have been deposited in the online IFNGR1 variation database (www.LOVD.nl/IFNGR1). In this article, we review the function of IFN-gamma R1 andmolecular genetics of human IFNGR1.