The genetic heterogeneity of mendelian susceptibility to mycobacterial diseases
2008; Elsevier BV; Volume: 122; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2008.10.037
ISSN1097-6825
AutoresSaleh Al‐Muhsen, Jean‐Laurent Casanova,
Tópico(s)Chronic Lymphocytic Leukemia Research
ResumoPrimary 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. 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. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: December 2008. Credit may be obtained for these courses until November 30, 2010.Copyright Statement: Copyright © 2008-2010. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members:Authors: Saleh Al-Muhsen, MD, and Jean-Laurent Casanova, MD, PhDActivity Objectives1. To define the inheritance patterns of mendelian susceptibility to mycobacterial diseases. 2. To describe the different clinical phenotypes associated with mendelian susceptibility to mycobacterial diseases, clinical presentation, and outcome. 3. To delineate the key pathways of host defense against mycobacteria that are altered in patients with mendelian susceptibility to mycobacterial diseases. 4. To describe the heterogeneous gene defects causing susceptibility to mycobacterial diseases.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: Saleh Al-Muhsen and Jean-Laurent Casanova have no significant relationships to disclose.The vast majority of known primary immunodeficiencies (PIDs) display mendelian inheritance, with mutations in single genes segregating with the morbid phenotype.1Ochs H. Smith C.I.E. Puck J. Primary Immunodeficiencies: a molecular and genetic approach.2nd ed. Oxford University Press, New York2007Google Scholar Polygenic, mitochondrial, and somatic PIDs remain rare, possibly because of insufficient exploration. However, care is required when distinguishing between mendelian and complex traits, because patients are not single-gene organisms. Many factors contribute to the phenotypic expression of mendelian PIDs: modifier genes and also possibly mitochondrial and somatic mutations, together with the infectious and inert environment.2Fischer A. Human primary immunodeficiency diseases.Immunity. 2007; 27: 835-845Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar In any case, the field of PIDs has clearly been revolutionized by discovery of the underlying molecular defect in many PIDs, largely through international collaborations. However, there remains no consensual definition and universal classification of PIDs, blurring the rapidly expanding boundaries of a field that has recently seen a large number of unforeseen disoveries.1Ochs H. Smith C.I.E. Puck J. Primary Immunodeficiencies: a molecular and genetic approach.2nd ed. Oxford University Press, New York2007Google Scholar, 3Geha R.S. Notarangelo L.D. Casanova J.L. Chapel H. Conley M.E. Fischer A. et al.Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee.J Allergy Clin Immunol. 2007; 120: 776-794Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar, 4Casanova Jl F.C. Zhang S.-Y. Abel L. revisiting human primary immunodeficiencies.J Intern Med. 2008; 264: 115-127Crossref PubMed Scopus (61) Google Scholar Leaving aside the difficult question of the definition of PIDs,4Casanova Jl F.C. Zhang S.-Y. Abel L. revisiting human primary immunodeficiencies.J Intern Med. 2008; 264: 115-127Crossref PubMed Scopus (61) Google Scholar, 5Casanova J.L. Fieschi C. Bustamante J. Reichenbach J. Remus N. von Bernuth H. et al.From idiopathic infectious diseases to novel primary immunodeficiencies.J Allergy Clin Immunol. 2005; 116: 426-430Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 6Casanova J.L. Abel L. Primary immunodeficiencies: a field in its infancy.Science. 2007; 317: 617-619Crossref PubMed Scopus (249) Google Scholar more than 200 clinical illnesses commonly considered to be PIDs have been described since the early 1950s, and more than 140 PID-causing genes have been identified, mostly since 1990.1Ochs H. Smith C.I.E. Puck J. Primary Immunodeficiencies: a molecular and genetic approach.2nd ed. Oxford University Press, New York2007Google Scholar, 3Geha R.S. Notarangelo L.D. Casanova J.L. Chapel H. Conley M.E. 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The prevalence of consanguineous marriages in an underserved area in Lebanon and its association with congenital anomalies.Genet Test. 2008; 12: 367-372Crossref PubMed Scopus (42) Google Scholar In the Iranian registry, the parents of 65% of all registered patients with conventional PIDs were found to be related to each other.16Rezaei N. Pourpak Z. Aghamohammadi A. Farhoudi A. Movahedi M. Gharagozlou M. et al.Consanguinity in primary immunodeficiency disorders: the report from Iranian Primary Immunodeficiency Registry.Am J Reprod Immunol. 2006; 56: 145-151Crossref PubMed Scopus (94) Google Scholar This high frequency of consanguinity has resulted in many PIDs being first described in patients originating from these countries (Fig 1).20Dupuis S. Jouanguy E. Al-Hajjar S. Fieschi C. Al-Mohsen I.Z. 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Oxford University Press, New York2007Google Scholar, 3Geha R.S. Notarangelo L.D. Casanova J.L. Chapel H. Conley M.E. Fischer A. et al.Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee.J Allergy Clin Immunol. 2007; 120: 776-794Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar Several PIDs display genetic heterogeneity, with several genetic defects causing the same or similar clinical syndromes. Mendelian susceptibility to mycobacterial diseases (MSMD) displays the highest level of genetic and allelic heterogeneity to date, with mutations in 6 genes accounting for 13 MSMD-causing genetic traits (Table I). We focus here on MSMD, highlighting the essential role of dissection of the 13 genetic traits for defining major variations of clinical presentation among patients with MSMD. New genetic etiologies of MSMD remain to be discovered, including new AR etiologies in particular, highlighting the tremendous power of forward genetics for investigating patients with PIDs.Table IGenetic heterogeneity of MSMDGeneChromosomal locationProtein affectedInheritanceFunctional impairmentProtein expressionIFNGR16q23-q24IFN-γ receptor ligand binding chainARCompleteYesARCompleteNoARPartialYesADPartialYes (abundant)IFNGR221q22.1-22.2IFN-γ receptor signal trasducing chainARCompleteYesARCompleteNoARPartialYesIL12B5q31.1-33.1IL-12 p40 subunitARCompleteNoIL12RB119p13.1IL-12 receptor β-subunitARCompleteYesARCompleteNoStat12q32.2-32.3Signal transducer and activator of transcription 1ADPartialYes, with impaired phosphorylationADPartialYes, with impaired DNA-bindingNEMOXq28Nuclear factor-κB essential modulatorXRPartialYesThe 14 known genetic and clinical etiologies of MSMD. Open table in a new tab The 14 known genetic and clinical etiologies of MSMD. 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Tezcan I. et al.A case of interleukin-12 receptor beta-1 deficiency with recurrent leishmaniasis.Pediatr Infect Dis J. 2007; 26: 366-368Crossref PubMed Scopus (33) Google Scholar and some viruses, such as human herpes virus-8.33Camcioglu Y. Picard C. Lacoste V. Dupuis S. Akcakaya N. Cokura H. et al.HHV-8-associated Kaposi sarcoma in a child with IFNgammaR1 deficiency.J Pediatr. 2004; 144: 519-523Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Some of these infections may have pathogenic mechanisms in common with MSMD, because their macrophage tropism and clinical features resemble those of mycobacteriosis, but it is difficult to establish a causal relationship from single case reports (Table II).Table IIClinical characteristics of different MSMD phenotypesPrognosisIndication for IFN-γOther organisms∗Anecdotal case reports and casual relation need to be established.Salmonella infectionMycobacterial infectionClinical diseasePoorNoHHV-8, CMV, Listeria Monocytogenes++++ BCG and EMAR complete IFNGR1 defectGoodYes–++++ (BCG, EM and MTb)AR partial IFNGR1 defectFairYesVZV, H capsulatum++++ (BCG, EM) MAC osteomyelitisAD partial IFNGR1 defectPoorNo–++++ BCG and EMAR complete IFNGR2 defectGoodYes–++++ BCGAR partial IFNGR2 defect†Only a single patient was reported.FairYes?++++++ (BCG) + (EM and MTb)IL12p40 defectFairYesKlebsiella, Leishmania, P brasiliensis++++++ (BCG) ++ (EM and MTb)IL12RB1 defectGoodYes––+++ (BCG, EM, MAC)Stat1 defectVariable?Hib (invasive disease)–+++ (MAC, EM)XR NEMO defectThe clinical variability, common infections, and prognosis of different types of MSMD.Hib, Hemophilus influenza type b; MAC, M avium complex; MTb, M tuberculosis.∗ Anecdotal case reports and casual relation need to be established.† Only a single patient was reported. Open table in a new tab The clinical variability, common infections, and prognosis of different types of MSMD. Hib, Hemophilus influenza type b; MAC, M avium complex; MTb, M tuberculosis. We have begun to understand the genetic etiology of MSMD over the last 12 years. As detailed in this review, germline mutations have been identified in 5 autosomal (IFN-γ receptor 1 [IFNGR1], IFN-γ receptor 2 [IFNGR2], signal transducer and activator of transcription 1 [STAT1], IL-12 B p40 subunit [IL12B], and IL-12 receptor β-subunit [IL12RB1]) genes and 1 X-linked (nuclear factor-κB–essential modulator [NEMO]) gene causing MSMD. These genes display a high level of heterogeneity, with multiple mutations at each locus and various sets of alleles, defining 13 distinct mendelian traits, differing in their mode of inheritance or the expression or functional status of the mutant molecule. For example, there are complete and partial forms of IFN-γ receptor 1 deficiency, and the partial forms may display AR or AD inheritance (Table I). However, no genetic etiology has yet been identified in at least 50% of patients with MSMD, despite these advances (J.-L. Casanova, unpublished data, August 2008). The proportions of XR, AD, and AR MSMD-causing mendelian traits probably reflect the distribution of these types of inheritance among PIDs. AR traits are the leading causes of MSMDs and PIDs. In keeping with the theme of this issue of the Journal, we review MSMD from a mendelian genetic perspective, as an example of a PID with a high level of genetic and allelic heterogeneity. 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.34Casanova J.L. Jouanguy E. Lamhamedi S. Blanche S. Fischer A. 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