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Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.

Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, AlSum Z, Al-Jumaah S, Al-Hajjar S, Frayha H, Alangari A, Al-Mousa H, Mobaireek KF, Ben-Mustapha I, Adimi P, Feinberg J, de Suremain M, Jannière L, Filipe-Santos O, Mansouri N, Stephan JL, Nallusamy R, Kumararatne DS, Bloorsaz MR, Ben-Ali M, Elloumi-Zghal H, Chemli J, Bouguila J, Bejaoui M, Alaki E, AlFawaz TS, Al Idrissi E, ElGhazali G, Pollard AJ, Murugasu B, Wah Lee B, Halwani R, Al-Zahrani M, Al Shehri MA, Al-Zahrani M, Bin-Hussain I, Mahdaviani SA, Parvaneh N, Abel L, Mansouri D, Barbouche R, Al-Muhsen S, Casanova JL - Medicine (Baltimore) (2013)

Bottom Line: Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries.As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ).In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

View Article: PubMed Central - PubMed

Affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.

ABSTRACT
Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

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Pedigrees of 30 families with IL-12p40 deficiency. Each kindred is designated by an integer (numbers 1–30), each generation is designated by a roman numeral (numerals I–II), and each individual by an arabic numeral (each individual studied is identified by these 3 numbers, organized from left to right). Symbols are split in 2 by a horizontal line. The upper part of the symbol indicates mycobacterial infection (black for BCG or atypical mycobacteriosis, gray for tuberculosis); the lower part of the symbol indicates salmonellosis status (black indicating the patient has had salmonellosis). The probands are indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?” Asymptomatic individuals carrying 2 mutant IL12B alleles are represented by a vertical line.
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F1-6: Pedigrees of 30 families with IL-12p40 deficiency. Each kindred is designated by an integer (numbers 1–30), each generation is designated by a roman numeral (numerals I–II), and each individual by an arabic numeral (each individual studied is identified by these 3 numbers, organized from left to right). Symbols are split in 2 by a horizontal line. The upper part of the symbol indicates mycobacterial infection (black for BCG or atypical mycobacteriosis, gray for tuberculosis); the lower part of the symbol indicates salmonellosis status (black indicating the patient has had salmonellosis). The probands are indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?” Asymptomatic individuals carrying 2 mutant IL12B alleles are represented by a vertical line.

Mentions: We identified 30 kindreds, comprising a total of 49 IL12p40-deficient patients (30 index cases and 19 sibs), including 44 symptomatic and 5 asymptomatic subjects (Table 1, Figure 1). Detailed pedigrees were available for 29 families, 25 (86.2%) of which were consanguineous (mostly due to first-cousin marriages). Sequencing of the 6 IL12B coding exons and flanking intron regions in the 30 index cases from 5 different countries (India, Iran, Saudi Arabia, Pakistan, and Tunisia) revealed only 9 different mutant IL12B alleles (Figure 2), 5 of which had not previously been reported (Figure 3). The known mutations were 2 small deletions (526del2, 297del8),16,32 1 insertion (315insA),14,30 and 1 large deletion (g.482+82_856-854del).33 All 4 known mutations induced frameshifts, resulting in the generation of premature termination codons (526del2, 297del8, 35del10, 315insA) or the excision of 2 coding exons (g.482+82_856-854del). The 5 newly identified IL12B mutations comprised 1 deletion (35del10), 1 insertion (909insA), 1 nonsense mutation (W60X), and 2 splice-site mutations (697+2T>C and 697+5G>A). Each of these mutations was found in a single kindred. These previously unknown mutations had a major impact on the structure of the IL12B mRNA. The splice-site mutations (697+2T>C and 697+5G>A) led to the excision of exon 6 and an absence of full-length IL12 mRNA, as shown by RT-PCR (data not shown). The 909insA mutation resulted in the insertion of a premature stop codon at amino acid 307. The most prevalent IL12B mutation was the previously reported 315insA mutation, which was detected only in patients from Saudi Arabia (n = 24; 13 kindreds). The next most frequent mutation was the 297del8 mutation, which was identified exclusively in kindreds originating from Tunisia (n = 8; 5 kindreds).14,33


Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.

Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, AlSum Z, Al-Jumaah S, Al-Hajjar S, Frayha H, Alangari A, Al-Mousa H, Mobaireek KF, Ben-Mustapha I, Adimi P, Feinberg J, de Suremain M, Jannière L, Filipe-Santos O, Mansouri N, Stephan JL, Nallusamy R, Kumararatne DS, Bloorsaz MR, Ben-Ali M, Elloumi-Zghal H, Chemli J, Bouguila J, Bejaoui M, Alaki E, AlFawaz TS, Al Idrissi E, ElGhazali G, Pollard AJ, Murugasu B, Wah Lee B, Halwani R, Al-Zahrani M, Al Shehri MA, Al-Zahrani M, Bin-Hussain I, Mahdaviani SA, Parvaneh N, Abel L, Mansouri D, Barbouche R, Al-Muhsen S, Casanova JL - Medicine (Baltimore) (2013)

Pedigrees of 30 families with IL-12p40 deficiency. Each kindred is designated by an integer (numbers 1–30), each generation is designated by a roman numeral (numerals I–II), and each individual by an arabic numeral (each individual studied is identified by these 3 numbers, organized from left to right). Symbols are split in 2 by a horizontal line. The upper part of the symbol indicates mycobacterial infection (black for BCG or atypical mycobacteriosis, gray for tuberculosis); the lower part of the symbol indicates salmonellosis status (black indicating the patient has had salmonellosis). The probands are indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?” Asymptomatic individuals carrying 2 mutant IL12B alleles are represented by a vertical line.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3822760&req=5

F1-6: Pedigrees of 30 families with IL-12p40 deficiency. Each kindred is designated by an integer (numbers 1–30), each generation is designated by a roman numeral (numerals I–II), and each individual by an arabic numeral (each individual studied is identified by these 3 numbers, organized from left to right). Symbols are split in 2 by a horizontal line. The upper part of the symbol indicates mycobacterial infection (black for BCG or atypical mycobacteriosis, gray for tuberculosis); the lower part of the symbol indicates salmonellosis status (black indicating the patient has had salmonellosis). The probands are indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?” Asymptomatic individuals carrying 2 mutant IL12B alleles are represented by a vertical line.
Mentions: We identified 30 kindreds, comprising a total of 49 IL12p40-deficient patients (30 index cases and 19 sibs), including 44 symptomatic and 5 asymptomatic subjects (Table 1, Figure 1). Detailed pedigrees were available for 29 families, 25 (86.2%) of which were consanguineous (mostly due to first-cousin marriages). Sequencing of the 6 IL12B coding exons and flanking intron regions in the 30 index cases from 5 different countries (India, Iran, Saudi Arabia, Pakistan, and Tunisia) revealed only 9 different mutant IL12B alleles (Figure 2), 5 of which had not previously been reported (Figure 3). The known mutations were 2 small deletions (526del2, 297del8),16,32 1 insertion (315insA),14,30 and 1 large deletion (g.482+82_856-854del).33 All 4 known mutations induced frameshifts, resulting in the generation of premature termination codons (526del2, 297del8, 35del10, 315insA) or the excision of 2 coding exons (g.482+82_856-854del). The 5 newly identified IL12B mutations comprised 1 deletion (35del10), 1 insertion (909insA), 1 nonsense mutation (W60X), and 2 splice-site mutations (697+2T>C and 697+5G>A). Each of these mutations was found in a single kindred. These previously unknown mutations had a major impact on the structure of the IL12B mRNA. The splice-site mutations (697+2T>C and 697+5G>A) led to the excision of exon 6 and an absence of full-length IL12 mRNA, as shown by RT-PCR (data not shown). The 909insA mutation resulted in the insertion of a premature stop codon at amino acid 307. The most prevalent IL12B mutation was the previously reported 315insA mutation, which was detected only in patients from Saudi Arabia (n = 24; 13 kindreds). The next most frequent mutation was the 297del8 mutation, which was identified exclusively in kindreds originating from Tunisia (n = 8; 5 kindreds).14,33

Bottom Line: Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries.As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ).In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

View Article: PubMed Central - PubMed

Affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.

ABSTRACT
Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Show MeSH
Related in: MedlinePlus