A purely quantitative form of partial recessive IFN-?R2 deficiency caused by mutations of the initiation or second codon.

ABSTRACT: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-? immunity. Germline bi-allelic mutations of IFNGR2 can underlie partial or complete forms of IFN-? receptor 2 (IFN-?R2) deficiency. Patients with partial IFN-?R2 deficiency express a dysfunctional molecule on the cell surface. We studied three patients with MSMD from two unrelated kindreds from Turkey (P1, P2) and India (P3), by whole-exome sequencing. P1 and P2 are homozygous for a mutation of the initiation codon(c.1A>G) of IFNGR2, whereas P3 is homozygous for a mutation of the second codon (c.4delC). Overexpressed mutant alleles produce small amounts of full-length IFN-?R2 resulting in an impaired, but not abolished, response to IFN-?. Moreover, SV40-fibroblasts of P1 and P2 responded weakly to IFN-?, and Epstein Barr virus-transformed B cells had a barely detectable response to IFN-?. Studies in patients' primary T cells and monocyte-derived macrophages yielded similar results. The residual expression of IFN-?R2 protein of normal molecular weight and function is due to the initiation of translation between the second and ninth non-AUG codons. We thus describe mutations of the first and second codons of IFNGR2, which define a new form of partial recessive IFN-?R2 deficiency. Residual levels of IFN-? signaling were very low, accounting for the more severe clinical phenotype of these patients with residual expression levels of normally functional surface receptors than of patients with partial recessive IFN-?R2 deficiency due to surface-expressed dysfunctional receptors, whose residual levels of IFN-? signaling were higher.

SUBMITTER: Oleaga-Quintas C 

PROVIDER: S-EPMC6216222 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature