Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome 
conferring predisposition to clinical disease caused by weakly virulent 
mycobacteria, such as Mycobacterium bovis 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, NEMO and CYBB, have long been known to cause other human 
diseases-incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with 
immunodeficiency (EDA-ID) (NEMO/IKKG), and X-linked chronic granulomatous 
disease (CGD) (CYBB)-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 NEMO 
selectively affect the CD40-dependent induction of IL-12 in mononuclear cells. 
CYBB encodes gp91(phox) , which is an essential component of the NADPH oxidase 
in phagocytes. The MSMD-causing mutation in CYBB selectively affects the 
respiratory burst in macrophages. Mutations in NEMO and CYBB may therefore cause 
MSMD by selectively exerting their deleterious impact on a single signaling 
pathway (CD40-IL-12, NEMO) or a single cell type (macrophages, CYBB). 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.