title: A point mutation in a domain of gamma interferon receptor 1 provokes severe immunodeficiency.
abstract: Gamma interferon (IFN-gamma) and the cellular responses induced by it are essential for controlling mycobacterial infections. Most patients bearing an IFN-gamma receptor ligand-binding chain (IFN-gammaR1) deficiency present gross mutations that truncate the protein and prevent its expression, giving rise to severe mycobacterial infections and, frequently, a fatal outcome. In this report a new mutation that affects the IFN-gammaR1 ligand-binding domain in a Spanish patient with mycobacterial disseminated infection and multifocal osteomyelitis is characterized. The mutation generates an amino acid change that does not abrogate protein expression on the cellular surface but that severely impairs responses after the binding of IFN-gamma (CD64 and HLA class II induction and tumor necrosis factor alpha and interleukin-12 production). A patient's younger brother, who was also probably homozygous for the mutation, died from meningitis due to Mycobacterium bovis. These findings suggest that a point mutation may be fatal when it affects functionally important domains of the receptor and that the severity is not directly related to a lack of IFN-gamma receptor expression. Future research on these nontruncating mutations will make it possible to develop new therapeutical alternatives in this group of patients.
authors.affiliation: Department of Immunology, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, 28041 Madrid, Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Allende
authors.forename: A
authors.initials: A
authors.lastname: López-Goyanes
authors.forename: E
authors.initials: E
authors.lastname: Paz-Artal
authors.forename: A
authors.initials: A
authors.lastname: Corell
authors.forename: M A
authors.initials: MA
authors.lastname: García-Pérez
authors.forename: P
authors.initials: P
authors.lastname: Varela
authors.forename: A
authors.initials: A
authors.lastname: Scarpellini
authors.forename: S
authors.initials: S
authors.lastname: Negreira
authors.forename: E
authors.initials: E
authors.lastname: Palenque
authors.forename: A
authors.initials: A
authors.lastname: Arnaiz-Villena
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009165:Mycobacterium Infections, Nontuberculous / Q000235:genetics* / Q000378:metabolism; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection / Q000235:genetics* / Q000378:metabolism; D009170:Nontuberculous Mycobacteria; D010019:Osteomyelitis / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D017471:Receptors, Interferon / Q000235:genetics* / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor