Genetic heterogeneity of Mendelian susceptibility to mycobacterial infection

Mendelian susceptibility to poorly virulent mycobacterial species, such as bacillus Calmette-Guerin (BCG) and environmental nontuberculous mycobacteri a (NTM), is a phenotypically heterogeneous syndrome. It has therefore long been suspected to be genetically heterogeneous. In the past 5 years, this p rediction has been confirmed and different types of mutations (dominant or recessive, nonfunctional or hypofunctional) in four genes (IFNGR1, IFNGR2, IL12B, IL12RB1) have revealed both allelic and nonallelic heterogeneity. Th e eight disorders resulting from these mutations are genetically different but immunologically related, as impaired IFN-gamma -mediated immunity is th e common pathogenic mechanism accounting for mycobacterial infection in all patients. The severity of the phenotype depends on the genotype. Complete IFN-gamma R1 and IFN-gamma R2 deficiencies predispose patients to a more se vere clinical course than partial IFN-gamma R1 and IFN-gamma R2 deficiencie s and complete IL-12 p40 and IL-12R beta1 deficiencies. (C) 2000 Editions s cientifiques et medicales Elsevier SAS.