Human Mutation
Human Mutation
5 years ago

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

IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database
Esther de Vosse, Jaap T. Dissel
IFN-γ signaling is essential for the innate immune defense against mycobacterial infections. IFN-γ signals through the IFN-γ receptor, which consists of a tetramer of two IFN-γR1 chains in complex with two IFN-γR2 chains, where IFN-γR1 is the ligand-binding chain of the interferon-γ receptor and IFN-γR2 is the signal-transducing chain of the IFN-γ receptor. Germline mutations in the gene IFNGR1 encoding the IFN-γR1 cause a primary immunodeficiency that mainly leads to mycobacterial 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-γR1 and molecular genetics of human IFNGR1. Signal transduction through the IFN-γ Receptor. Left: IFN-γR1 and IFN-γR2 chain. Middle: two IFN-γR1 and two IFN-γR2 chains bind their respective JAKs and preassemble to form the tetrameric IFN-γ receptor. Right: After IFN-γ binds to the IFN-γ receptor complex, STAT1 is phosphorylated (pSTAT1). pSTAT1 molecules form anti-parallel homodimers (GAF), that are released from the receptor and translocate to the nucleus where they bind to the gamma-interferon-activated sites (GAS) in the promoters of various genes to initiate transcription.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/humu.23302

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