Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency - 29/04/13
, Tobias Rausch, PhD b, , Thomas Giese, MD c, , Obul R. Bandapalli, PhD a, Volker Daniel, MD c, Isabelle Bekeredjian-Ding, MD d, Adrian M. Stütz, PhD b, Christoph Drees, MD e, Susanne Roth, MD e, Jürgen Ruland, MD e, Jan O. Korbel, PhD b, ⁎ 
, Andreas E. Kulozik, MD, PhD a, ⁎ Corresponding authors: Jan O. Korbel, PhD, Genome Biology Unit, EMBL, Meyerhofstr. 1, 69117 Heidelberg, Germany.Andreas E. Kulozik, MD, PhD, Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 430, Heidelberg D-69120, Germany.Abstract |
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-of-function 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 κB activation.
Conclusion |
We show that an inactivating CARD11 mutation links defective nuclear factor κB signaling to a novel cause of autosomal recessive SCID.
Le texte complet de cet article est disponible en PDF.Key words : Whole-exome sequencing, systematic variant categorization, caspase recruitment domain 11 (CARD11), severe combined immunodeficiency, T cell, B cell, nuclear factor κB, infection
Abbreviations used : BCR, CARD, GATK, NF-κB, PKC, PMA, SCID, SNV, TCR, WT
Plan
| Supported by the Dietmar Hopp Stiftung and the German Research Foundation (DFG) SFB grants (to J.R.). J.O.K. was supported by an Emmy Noether Fellowship (KO 4037/1-1) from the DFG. I.B.-D. was supported by DFG grant BE3841/2-1. |
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| Disclosure of potential conflict of interest: I. Bekeredjian-Ding has received grants from Deutsche Forschungsgemeinschaft (German Research Association). The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 5
P. 1376 - mai 2013 Retour au numéro
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