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-γ 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-γ receptor 1 gene mutations. Patient 1 became ill after Bacillus CalmetteGuérin 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-γ receptor 1 protein, resulting in the lack of detectable protein expression and absence of interferon-γ 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-γ receptor 1 protein with absence of the transmembrane domain. Protein expression and interferon-γ dependent signaling were not detectable.

Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

“…HSCT was considered successful for five patients at the time at which their cases were reported [85, 111–113]. The oldest surviving patient was 19 years old in 2007 and had suffered six episodes of mycobacterial infection, each treated with antibiotics for six to nine months [97]. …”

Inborn errors of interferon (IFN)‐mediated immunity in humans: insights into the respective roles of IFN‐α/β, IFN‐γ, and IFN‐λ in host defense

“…Cells from patients with PR or PD deficiency display an impaired but not abolished response. BCG and EM are the leading causes of disease in all IFN‐γR1‐deficient patients (23, 25, 32–39, 44, 48, 55). One patient had clinical tuberculosis (34, 56), about 4% had salmonellosis (23, 48), with a smaller proportion presenting viral infections (46, 57), histoplasmosis (47), and listeriosis (41).…”

The genetic heterogeneity of mendelian susceptibility to mycobacterial diseases

“…49 The oldest surviving patient is now 20 years old and has experienced several mycobacterial infections in his lifetime. 52 Treatment with IFN-g is not indicated because of the lack of specific receptors. The prognosis is poor, and the only curative option is hematopoietic stem cell transplantation (HSCT).…”