title: Two patients with complete defects in interferon gamma receptor-dependent signaling.
abstract: Unusual susceptibility to mycobacterial infections can be caused by deleterious mutations in genes that encode the interferon-gamma receptor 1 chain. Such mutations hamper the activation of macrophages by a type 1 immune response and result in enhanced survival of intracellular pathogens. We here report two patients with unusual mycobacterial infections, both diagnosed with homozygous deleterious interferon-gamma receptor 1 gene mutations. Patient 1 became ill after Bacillus Calmette-Guérin vaccination at the age of 9 months and died at the age of 18 months. She carried a homozygous C71Y mutation in the extracellular part of the mature interferon-gamma receptor 1 protein, resulting in the lack of detectable protein expression and absence of interferon-gamma dependent signaling. Patient 2 became ill at the age of 3 years, is still alive at 19 years of age, and has suffered from five successive infection episodes with atypical mycobacteria. A homozygous splice-site mutation in intron 3 was identified, resulting in the deletion of exon 3 at the mRNA level and consequently a truncated interferon-gamma receptor 1 protein with absence of the transmembrane domain. Protein expression and interferon-gamma dependent signaling were not detectable.
authors.affiliation: Department of Immunology, Erasmus MC/University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jeroen G
authors.initials: JG
authors.lastname: Noordzij
authors.forename: Nico G
authors.initials: NG
authors.lastname: Hartwig
authors.forename: Frank A W
authors.initials: FA
authors.lastname: Verreck
authors.forename: Sandra
authors.initials: S
authors.lastname: De Bruin-Versteeg
authors.forename: Tjitske
authors.initials: T
authors.lastname: De Boer
authors.forename: Jaap T
authors.initials: JT
authors.lastname: Van Dissel
authors.forename: Ronald
authors.initials: R
authors.lastname: De Groot
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: Van Dongen
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D007223:Infant; D008297:Male; D009164:Mycobacterium Infections / Q000235:genetics / Q000276:immunology; D017354:Point Mutation; D022821:RNA Splice Sites / Q000235:genetics; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D022821:RNA Splice Sites; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor