A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

Abstract

The immunogenetic basis of severe infections caused by bacille Calmette-Guérin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.

Disseminated Mycobacterium avium Complex Infection in a Child with Partial Dominant Interferon Gamma Receptor 1 Deficiency in India

“…Newport et al and Jouanguy et al described the first bi-allelic mutations of IFNGR1 conferring complete IFN-γR1 deficiency [3,4,6]. Three different forms of IFN-γR1 deficiency have been described: complete, partial recessive (PR) and partial dominant (PD) [2].…”

Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors

“…To list a few examples of this diversity: (1) the disease severity in the connective tissue disorder Marfan syndrome correlates with the abundance of the PTC? fibrillin 1 (FBN1) mRNA [29], (2) PTCs at different positions in CFTR (cystic fibrosis transmembrane-conductance regulator) can cause mild to severe cystic fibrosis [30], and (3) truncated forms of IFNGR1 (interferon gamma receptor 1) can result in recessively or dominantly inherited susceptibility to mycobacterial infections [31,32].…”

Adjunctive treatment of disseminated Mycobacterium avium complex infection with interferon alpha-2b in a patient with complete interferon-gamma receptor R1 deficiency

“…IFNGR1 deficiency is caused by allelic dominant and recessive mutations [8,29]. Most recessive IFNGR1 deficiencies present complete lack of responses to IFN-γ, either by lack of IFN-γ receptor expression [3, 6, 13, 15-17, 20, 23, 26, 27, 30, 31, 33], as shown in this case, or by failure to recognize the ligand IFN-γ [2,16]. Clinical features of IFNGR1 are characterized by a very narrow spectrum of opportunistic infections, mostly limited to environmental mycobacteria and Mycobacterium bovis bacillus CalmetteGuérin (BCG), although serious infections with H. capsulatum and Listeria monocytogenes have been reported [8,9,12,29].…”