Mendelian susceptibility to mycobacterial disease: 2014-2018 update

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. Since 1996, disease-causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase-like 2 A deficiency, (2) TYK2-deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN-γR2 deficiency, and (4) two forms of syndromic MSMD: RORγ/RORγT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.

Keywords: IFN-γ; mycobacterium; next-generation sequencing; primary immunodeficiency.

Figure 1 –. Genetic spectrum of MSMD (a) Geographic distribution of patients with MSMD. (b) Cells involved in the production of and response to IFN-γ.

Proteins for which a mutation of the corresponding gene has been recognized to cause solely MSMD (IFN-γR1, IFN-γR2, SPPL2a, NEMO, gp91^phox, IL-12p40, IL-12Rβ1, ISG15) are depicted in black, those responsible for syndromic MSMD (JAK1, RORγ) are depicted with vertical lines, those that can cause either MSMD or syndromic MSMD (IRF8, STAT1, TYK2) are depicted with crossed lines.