Reviews and feature article
The genetic heterogeneity of mendelian susceptibility to mycobacterial diseases

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Primary immunodeficiencies (PIDs) were long thought to be exclusively recessive traits — autosomal recessive (AR) in most cases, with a few X-linked recessive (XR) diseases. In recent years, autosomal dominant (AD), mitochondrial, polygenic, and even somatic PIDs have been described. However, AR remains the most frequent inheritance pattern among recently described PIDs. Some PIDs have been shown to be genetically heterogeneous. Mendelian susceptibility to mycobacterial diseases (MSMD) displays a high level of genetic heterogeneity. There are 6 MSMD-causing genes, including 1 X-linked gene (nuclear factor-κB–essential modulator [NEMO]) and 5 autosomal genes (IFN-γ receptor 1 [IFNGR1], IFN-γ receptor 2 [IFNGR2], signal transducer and activator of transcription 1 [STAT1], IL-12 p40 subunit [IL12P40], and IL-12 receptor β-subunit [IL12RB1]). The X-linked trait is XR; STAT1 deficiency is AD; the IFNGR2, IL12P40 subunit, and IL12RB1 deficiencies are AR; and IFNGR1 deficiency may be AD or AR. Two of the AR traits (IFNGR1, IFNGR2) may be subdivided into complete and partial deficiencies, and 3 AR complete deficiencies (IFNGR1, IFNGR2, IL12RB1) may be subdivided into disorders with and without cell surface expression. Finally, there are 2 types of AD STAT1 deficiency, depending on whether the mutation impairs phosphorylation or DNA binding. Thirteen genetic disorders conferring MSMD have been described, involving 1 XR, 3 AD (2 genes), and 9 AR traits (4 genes). However, no genetic etiology has yet been identified for about half of all patients with MSMD. We expect to identify new XR and AD causes of MSMD, but new AR etiologies of MSMD are also likely to be discovered. The investigation of children from areas in which consanguineous marriages are common will probably facilitate the description of many more AR traits.

Section snippets

MSMD

Mendelian susceptibility to mycobacterial diseases (Mendelian inheritance in man 209,950)23 is a rare congenital syndrome conferring a predisposition to infections caused by weakly virulent mycobacteria, such as BCG vaccines and nontuberculous environmental mycobacteria (EM).24 Affected individuals are also vulnerable to the more virulent mycobacterial species Mycobacterium tuberculosis.25 Systemic salmonellosis, either typhoidal or, more commonly, nontyphoidal, is encountered in about 50% of

Complete and partial AR IFNGR1 deficiency

The high frequency of parental consanguinity and the occurrence of MSMD in siblings of unaffected parents suggested that MSMD was probably mostly inherited as an AR trait.34, 35, 36 Indeed, AR complete IFNGR1 deficiency was the first genetic etiology of MSMD to be identified at the molecular level, in 1996, in patients lacking expression of this receptor.37, 38 As many as 21 different causal mutations conferring AR complete IFNGR1 deficiency have since been identified, 17 of which, including

AD IFNGR1 deficiency

Dominant IFNGR1 deficiency was first reported in 1999.84 More than 60 patients bearing heterozygous mutations in the IFNGR1 gene have since been identified worldwide.49, 85, 86, 87, 88 Microdeletion 818del4 is by far the most common mutation39 (J.-L. Casanova, unpublished data, August 2008). Indeed, this microdeletion corresponds to the first documented hotspot for microdeletions in the human genome and results in the introduction of a premature stop codon into the proximal intracellular domain.

XR MSMD

An XR pattern of inheritance for MSMD was clinically suspected as early as 1991,90 with further evidence obtained in 1994.91 Four maternally related male patients in American multiplex kindred had disseminated M avium complex infection, with no evidence of other opportunistic infections. They displayed impaired T-cell–dependent IL-12 production, providing further evidence of the underlying genetic cause, different from that of other well recognized MSMD diseases.92, 93 Two mutations (E315A and

Perspectives

The search for mitochondrial, somatic, and polygenic lesions is a promising line of research in the field of PIDs. AD traits are increasingly being identified. The apparently sporadic nature of some PIDs may well be explained by such modes of inheritance. XR traits are often familial, and it is likely that only a few X-linked PID genes remain to be discovered. By contrast, the number of AR PIDs seems to increase incessantly. MSMD provides a good example, with 9 AR etiologies already identified

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