Lethal Tuberculosis in a Previously Healthy Adult with IL-12 Receptor Deficiency

Tabarsi, Payam; Marjani, Majid; Mansouri, Nahal; Farnia, Parissa; Boisson–Dupuis, Stéphanie; Bustamante, Jacinta; Abel, Laurent; Adimi, Parisa; Casanova, Jean‐Laurent; Mansouri, Davood

doi:10.1007/s10875-011-9523-9

Cited by 46 publications

(36 citation statements)

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“…[1][2][3][4] Infections generally occur in children, with a wide range of clinical symptoms, from localized to disseminated infections. [1][2][3] The patients are also vulnerable to the more virulent Mycobacterium tuberculosis, [5][6][7] and about half of them also suffer from nontyphoidal Salmonella infection. 8,9 Other infections are increasingly documented, albeit typically in individual patients.…”

Section: Introductionmentioning

confidence: 99%

Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation

Moncada-Vélez

Martı́nez-Barricarte

Bogunovic

et al. 2013

Blood

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Key Points• Hypomorphic IFNGR2 alleles encode misfolded proteins with abnormal N-glycosylation.• Chemical modifiers of N-glycosylation effectively complemented the patients' response to IFN-g.We report a molecular study of the two known patients with autosomal recessive, partial interferon-g receptor (IFN-gR)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-gR2 levels on the surface of the three latter patients' cells are slightly lower than those on control cells. The patients' cells also display impaired, but not abolished, response to IFN-g. Moreover, the R114C, S124F, G141R and G227R IFNGR2 hypomorphic alleles all encode misfolded proteins with abnormal N-glycosylation.The mutants are largely retained in the endoplasmic reticulum, although a small proportion reach and function at the cell surface. Strikingly, the IFN-g response of the patients' cells is enhanced by chemical modifiers of N-glycosylation, as previously shown for patients with gain-of-glysosylation T168N and misfolding 382-387dup null mutations. All four in-frame IFNGR2 hypomorphic mutant alleles encoding surface-expressed receptors are thus deleterious by a mechanism involving abnormal N-glycosylation and misfolding of the IFN-gR2 protein. The diagnosis of partial IFN-gR2 deficiency is clinically useful, as affected patients should be treated with IFN-, unlike patients with complete IFN-gR2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-gR2 deficiency due to misfolding or gain

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Section: Introductionmentioning

confidence: 99%

Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation

Moncada-Vélez

Martı́nez-Barricarte

Bogunovic

et al. 2013

Blood

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“…These observations raise fundamental questions about the mechanisms underlying incomplete penetrance and variable expressivity that have yet to be answered. In this context, we serendipitously discovered the first cases (to our knowledge) of monogenic tuberculosis, in patients and even in families with IL-12Rβ1 deficiency manifesting solely as severe tuberculosis (86)(87)(88)(89)(90)(91). These patients were normally resistant to live bacillus Calmette-Guérin vaccine and environmental mycobacteria.…”

Section: Invasive Dermatophytosismentioning

confidence: 95%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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“…Inversely, infections with various salmonella can occur repeatedly. Infections with other pathogens such as candida [Cardenes et al, 2010; de Beaucoudrey et al, 2010] and, occasionally, M. tuberculosis have also been observed [Caragol et al, 2003; Özbek et al, 2005; de Beaucoudrey et al, 2010; Tabarsi et al, 2011; Boisson-Dupuis et al, 2011]. …”

Section: Introductionmentioning

confidence: 99%

IL-12Rβ1 Deficiency: Mutation Update and Description of theIL12RB1Variation Database

et al. 2013

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IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rβ1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rβ1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rβ1 and molecular genetics of human IL12RB1.

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Lethal Tuberculosis in a Previously Healthy Adult with IL-12 Receptor Deficiency

Cited by 46 publications

References 10 publications

Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation

Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation

Severe infectious diseases of childhood as monogenic inborn errors of immunity

IL-12Rβ1 Deficiency: Mutation Update and Description of theIL12RB1Variation Database

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