Genetic lessons learned from X‐linked Mendelian susceptibility to mycobacterial diseases

<jats:p>Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome conferring predisposition to clinical disease caused by weakly virulent mycobacteria, such as <jats:italic>Mycobacterium bovis</jats:italic> Bacille Calmette Guérin (BCG) vaccines and nontuberculous, environmental mycobacteria (EM). Since 1996, MSMD‐causing mutations have been found in six autosomal genes involved in IL‐12/23–dependent, IFN‐γ–mediated immunity. The aim of this review is to provide the description of the two described forms of X‐linked recessive (XR) MSMD. Germline mutations in two genes, <jats:italic>NEMO</jats:italic> and <jats:italic>CYBB</jats:italic>, have long been known to cause other human diseases—incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA‐ID) (<jats:italic>NEMO/IKKG</jats:italic>), and X‐linked chronic granulomatous disease (CGD) (<jats:italic>CYBB</jats:italic>)—but specific mutations in either of these two genes have recently been shown to cause XR‐MSMD. NEMO is an essential component of several NF‐κB–dependent signaling pathways. The MSMD‐causing mutations in <jats:italic>NEMO</jats:italic> selectively affect the CD40‐dependent induction of IL‐12 in mononuclear cells. <jats:italic>CYBB</jats:italic> encodes gp91<jats:italic><jats:sup>phox</jats:sup></jats:italic>, which is an essential component of the NADPH oxidase in phagocytes. The MSMD‐causing mutation in <jats:italic>CYBB</jats:italic> selectively affects the respiratory burst in macrophages. Mutations in <jats:italic>NEMO</jats:italic> and <jats:italic>CYBB</jats:italic> may therefore cause MSMD by selectively exerting their deleterious impact on a single signaling pathway (CD40–IL‐12, <jats:italic>NEMO</jats:italic>) or a single cell type (macrophages, <jats:italic>CYBB</jats:italic>). These experiments of Nature illustrate how specific germline mutations in pleiotropic genes can dissociate signaling pathways or cell lineages, thereby resulting in surprisingly narrow clinical phenotypes.</jats:p>