title: Congenital B cell lymphocytosis explained by novel germline CARD11 mutations.
abstract: Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions, but constitutive NF-κB activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)-induced NF-κB activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-κB activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.
authors.affiliation: Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA. andrew.snow@usuhs.edu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Snow
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Stinson
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chaigne-Delalande
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Helen F
authors.initials: HF
authors.lastname: Matthews
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.forename: Sameer
authors.initials: S
authors.lastname: Jhavar
authors.forename: Stefan
authors.initials: S
authors.lastname: Kuchen
authors.forename: Lela
authors.initials: L
authors.lastname: Kardava
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ian T
authors.initials: IT
authors.lastname: Lamborn
authors.forename: Huie
authors.initials: H
authors.lastname: Jing
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D016000:Cluster Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006162:Guanylate Cyclase / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015151:Immunoblotting; D008218:Lymphocytosis / Q000150:complications / Q000235:genetics*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010375:Pedigree; D013163:Splenomegaly / Q000150:complications
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; C426242:CARD11 protein, human; D006162:Guanylate Cyclase