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

• Verfasst von: Greil, Johann [VerfasserIn]
• Verfasst von: Rausch, Tobias [VerfasserIn]
• Verfasst von: Giese, Thomas [VerfasserIn]
• Verfasst von: Bandapalli, Obul Reddy [VerfasserIn]
• Verfasst von: Daniel, Volker [VerfasserIn]
• Verfasst von: Bekeredjian-Ding, Isabelle [VerfasserIn]
• Verfasst von: Stütz, Adrian M. [VerfasserIn]
• Verfasst von: Drees, Christoph [VerfasserIn]
• Verfasst von: Roth, Susanne [VerfasserIn]
• Verfasst von: Ruland, Jürgen [VerfasserIn]
• Verfasst von: Korbel, Jan Oliver [VerfasserIn]
• Verfasst von: Kulozik, Andreas [VerfasserIn]
• Titel: Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency
• Verf.angabe: Johann Greil, MD, Tobias Rausch, PhD, Thomas Giese, MD, Obul R. Bandapalli, PhD, Volker Daniel, MD, Isabelle Bekeredjian-Ding, MD, Adrian M. Stütz, PhD, Christoph Drees, MD, Susanne Roth, MD, Jürgen Ruland, MD, Jan O. Korbel, PhD, and Andreas E. Kulozik, MD, PhD
• E-Jahr: 2013
• Jahr: April 8, 2013
• Umfang: 11 S.
• Fussnoten: Gesehen am 25.02.2020
• Titel Quelle: Enthalten in: The journal of allergy and clinical immunology
• Ort Quelle: Amsterdam [u.a.] : Elsevier, 1971
• Jahr Quelle: 2013
• Band/Heft Quelle: 131(2013), 5, Seite 1376-1383.e3
• ISSN Quelle: 1097-6825
• DOI: doi:10.1016/j.jaci.2013.02.012
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: B cell
• Sach-SW: caspase recruitment domain 11 (CARD11)
• Sach-SW: infection
• Sach-SW: nuclear factor κB
• Sach-SW: severe combined immunodeficiency
• Sach-SW: systematic variant categorization
• Sach-SW: T cell
• Sach-SW: Whole-exome sequencing
• K10plus-PPN: 1749425734

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.