Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency.
J Allergy Clin Immunol
; 131(5): 1376-83.e3, 2013 May.
Article
em En
| MEDLINE
| ID: mdl-23561803
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Imunodeficiência Combinada Severa
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Proteínas Adaptadoras de Sinalização CARD
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Guanilato Ciclase
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
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Infant
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Alemanha