Inherited Interleukin-12 Deficiency: IL12B Genotype and Clinical Phenotype of 13 Patients from Six Kindreds Capucine Picard, Claire Fieschi, Frédéric.

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Inherited Interleukin-12 Deficiency: IL12B Genotype and Clinical Phenotype of 13 Patients from Six Kindreds Capucine Picard, Claire Fieschi, Frédéric Altare, Suliman Al-Jumaah, Sami Al-Hajjar, Jacqueline Feinberg, Stéphanie Dupuis, Claire Soudais, Ibrahim Zaid Al-Mohsen, Emmanuelle Génin, David Lammas, Dinakantha S. Kumararatne, Tony Leclerc, Arash Rafii, Husn Frayha, Belinda Murugasu, Lee Bee Wah, Raja Sinniah, Michael Loubser, Emi Okamoto, Abdulaziz Al-Ghonaium, Haysam Tufenkeji, Laurent Abel, Jean-Laurent Casanova The American Journal of Human Genetics Volume 70, Issue 2, Pages 336-348 (February 2002) DOI: 10.1086/338625 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of six families with IL12 deficiency caused by IL12B mutations. Each kindred is designated by a capital letter (A–F), each generation is designated by a roman numeral (I or II), and each individual is designated by an arabic numeral (1–8). Patients with mycobacteriosis and/or salmonellosis are represented by black symbols. The probands are indicated by arrows. “E?” indicates individuals for whom genetic analysis was not possible (e.g., B.II.1, who died of disseminated BCG infection at age 5 years). The American Journal of Human Genetics 2002 70, 336-348DOI: (10.1086/338625) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Impaired production of IL12. A, Production of IL12p70, IL12p40, and TNFα, by PDBu-stimulated EBV-B cells from a healthy positive control (C+) and a negative control (C−; A.II.1) (both of whom had previously been reported by Altare et al. [1998c]) and from patients (B.II.3, C.II.3, and D.II.4). Supernatants were harvested after 18 h of activation, for cytokine quantification by ELISA. The results are the mean ± SDs of two experiments. B, Production of IL12p70, IL12p40, and TNFα, by whole-blood cells from a healthy positive control (C+) and from patient D.II.4, either unstimulated (Medium) or stimulated with BCG plus IFNγ. Supernatants were harvested after 12 h of activation. C, Production of IFNγ by whole-blood cells from healthy positive control (C+) and from patient D.II.4, either unstimulated (Medium) or stimulated with BCG alone or with BCG plus recombinant IL12p70. The supernatants were harvested after 72 h of activation, for cytokine quantification by ELISA. The American Journal of Human Genetics 2002 70, 336-348DOI: (10.1086/338625) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 IL12B mutant alleles. A, Schematic representation of structural organization of coding region of wild-type (WT) IL12B gene. Exons I and VIII are not translated. Intrachain disulfite bounds and amino acids essential for dimerization with IL12p35 are indicated by the single-letter amino acid code. The positions of the two mutations found in IL12-deficient patients are also indicated. B, Schematic representation of coding region of two mutant IL12B alleles. Gray regions correspond to stretches of new amino acids resulting from the frameshift mutation. The American Journal of Human Genetics 2002 70, 336-348DOI: (10.1086/338625) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 High-resolution map of IL12B locus. A, Physical map of IL12B region on chromosome 5q33. The physical distances (in Mb) between IL12B and microsatellite markers were obtained from BLAST. B, Genomic organization of human IL12B gene and location of intragenic SNPs. White boxes indicate coding exons; gray boxes indicate untranslated exons. Translation initiation and termination codons are indicated. Arrows indicate positions of intragenic SNPs (−1356, 364+92, and 1146). The American Journal of Human Genetics 2002 70, 336-348DOI: (10.1086/338625) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 5 Haplotypes encompassing IL12B in patients with IL12 deficiency. Markers encompassing IL12B, with physical distance (Mb) and recombination rate (θ), are shown. Physical distance was obtained from BLAST; the recombination rate was estimated by use of the correspondence of .672 cM for 1 Mb, over the whole region, and use of the Kosambi mapping function (see the “Dating of Mutations” subsection). The ancestral haplotypes shared by kindreds A and B, from the Indian subcontinent, is indicated by dark-gray shading; the ancestral haplotype shared by kindreds C–F, from Saudi Arabia, is indicated by intermediate-gray shading; and the ancestral haplotype shared by a subset of kindreds is indicated by light-gray shading. The American Journal of Human Genetics 2002 70, 336-348DOI: (10.1086/338625) Copyright © 2002 The American Society of Human Genetics Terms and Conditions