IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity

Mutations in STAT3 and IL12RB1 impair the development of human IL-17 producing T cells

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Paternal Uniparental Isodisomy of Chromosome 6 Causing a Complex Syndrome Including Complete IFN-gamma Receptor 1 Deficiency

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency associated with clinical disease caused by weakly virulent mycobacterial species. Interferon gamma receptor 1 (IFN-γR1) deficiency is a genetic etiology of MSMD. We describe the clinical and genetic features of a seven-year-old Italian boy suffering from MSMD associated with a complex phenotype, including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features. The child also developed necrotizing pneumonia caused by Rhodococcus equi. The child is homozygous for a nonsense mutation in exon 3 of IFNGR1 as a result of paternal uniparental disomy (UPD) of the entire chromosome 6. This is the first reported case of uniparental disomy resulting in a complex phenotype including MSMD

Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease

Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This \u27experiment of nature\u27 indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria

Table indicating the clinical presentations of TB recorded in the fifty patients.

<p>The two patients presenting with IL-12Rβ1 deficiency are in bold. N means number and age is indicated in years.</p

Mendelian mutations in <i>IL12RB1</i> leading to severe tuberculosis in two kindreds.

<p><b>A</b>. Pedigree of the two families (A and B) with IL-12Rβ1 deficiency. Each generation is designated by a roman numeral (I–II), and each individual by an Arabic numeral. The double lines connecting the parents indicate consanguinity. The probands are indicated by an arrow, with black indicating <i>Mycobacterium tuberculosis</i> disease status. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?”. <b>B</b>. Electrophoregram showing the genomic sequences of exons 9 and 5 in patients 1 and 2, respectively, compared with a control sequence. <b>C</b>. Schematic diagram of the coding region of the IL-12Rβ1 chain containing 17 coding exons and encoding a 662-amino acid protein with a leader sequence (exon1, L), extracellular domain (exons 2 to 13, EC), transmembrane domain (exon 14, TM) and an intracellular cytoplasmic domain (exons 15 to 17, IC). Published and unpublished mutations are indicated as follows: missense mutations are shown in purple, nonsense mutations are shown in red and complex mutations are shown in brown. Splicing mutations are shown in blue, large deletions are shown in green, insertions are shown in orange, and duplication is shown in magenta. * The 700+362_1619-944del mutation is the only mutation resulting in at the expression of a protein at the cell surface. Mutations of P1 (K305X) and P2 (R173W) are underlined. <b>D</b>. Chest X ray of patient 1 showing the localization of the disease.</p