title: Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  We show that an inactivating CARD11 mutation links defective nuclear factor κB signaling to a novel cause of autosomal recessive SCID.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.forename: Tobias
authors.initials: T
authors.lastname: Rausch
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Obul R
authors.initials: OR
authors.lastname: Bandapalli
authors.forename: Volker
authors.initials: V
authors.lastname: Daniel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bekeredjian-Ding
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.forename: Christoph
authors.initials: C
authors.lastname: Drees
authors.forename: Susanne
authors.initials: S
authors.lastname: Roth
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D000595:Amino Acid Sequence; D053468:CARD Signaling Adaptor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D002460:Cell Line; D018389:Codon, Nonsense; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010375:Pedigree; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000235:genetics* / Q000276:immunology*
chemical_list: D053468:CARD Signaling Adaptor Proteins; D018389:Codon, Nonsense; C426242:CARD11 protein, human; D006162:Guanylate Cyclase