Two patients with complete defects in interferon gamma receptor-dependent signaling.
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.
Noordzij
Jeroen G
JG
Department of Immunology, Erasmus MC/University Medical Center Rotterdam, Rotterdam, The Netherlands.
Hartwig
Nico G
NG
Verreck
Frank A W
FA
De Bruin-Versteeg
Sandra
S
De Boer
Tjitske
T
Van Dissel
Jaap T
JT
De Groot
Ronald
R
Ottenhoff
Tom H M
TH
Van Dongen
Jacques J M
JJ
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
D022821:RNA Splice Sites; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor