Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency

被引:115
作者
Greil, Johann [1 ]
Rausch, Tobias [2 ]
Giese, Thomas [3 ]
Bandapalli, Obul R. [1 ]
Daniel, Volker [3 ]
Bekeredjian-Ding, Isabelle [4 ,5 ]
Stuetz, Adrian M. [2 ]
Drees, Christoph [6 ]
Roth, Susanne [6 ]
Ruland, Juergen [6 ]
Korbel, Jan O. [2 ]
Kulozik, Andreas E. [1 ]
机构
[1] Heidelberg Univ, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany
[2] EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany
[3] Heidelberg Univ, Inst Immunol, Heidelberg, Germany
[4] Heidelberg Univ, Dept Infect Dis Med Microbiol & Hyg, Heidelberg, Germany
[5] Univ Clin Bonn, IMMIP, Bonn, Germany
[6] Tech Univ Munich, Klinikum Rechts Isar, Inst Klin Chem & Pathobiochem, D-80290 Munich, Germany
关键词
Whole-exome sequencing; systematic variant categorization; caspase recruitment domain 11 (CARD11); severe combined immunodeficiency; T cell; B cell; nuclear factor kappa B; infection; NF-KAPPA-B; ACTIVATION; CARMA1; FAMILY; ASSOCIATION; REQUIREMENT; IMMUNOLOGY; MUTATIONS; ANTIGEN; INNATE;
D O I
10.1016/j.jaci.2013.02.012
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
Background: Primary immunodeficiencies represent model diseases for the mechanistic understanding of the human innate and adaptive immune response. They are clinically highly relevant per se because in patients with severe combined immunodeficiency (SCID), infections caused by opportunistic pathogens are typically life-threatening early in life. Objectives: We aimed at defining and functionally characterizing a novel form of SCID in an infant of consanguineous parents who presented with life-threatening Pneumocystis jirovecii pneumonia using a comprehensive immunologic and whole-exome genetic diagnostic strategy. Methods: Analysis of leukocyte subpopulations was performed by using multicolor flow cytometry and was combined with stimulation tests for T-cell function. The search for a disease-causing mutation was performed with diagnostic whole-exome sequencing and systematic variant categorization. Reconstitution assays were used for validating the loss-offunction mutation. Results: The novel entity of SCID was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T and B lymphocytes. Genetic analysis revealed a single pathogenic homozygous nonsense mutation of the caspase recruitment domain 11 (CARD11) gene. In reconstitution assays we demonstrated that the patient-derived truncated CARD11 protein is defective in antigen receptor signaling and nuclear factor kappa B activation. Conclusion: We show that an inactivating CARD11 mutation links defective nuclear factor kB signaling to a novel cause of autosomal recessive SCID.
引用
收藏
页码:1376 / U194
页数:11
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