Congenital B cell lymphocytosis explained by novel germline CARD11 mutations

• DOI: 10.1084/jem.20120831
• Publication Date: 2012-11-06T05:15:07Z
• Authors: Andrew L. Snow; Wenming Xiao; Jeffrey R. Stinson; Wei Lu; Benjamin Chaigne-...; Lixin Zheng; Stefania Pittaluga; Helen F. Matthews; Roland Schmitz; Sameer Jhavar; Stefan Kuchen; Lela Kardava; Wei Wang; Ian T. Lamborn; Huie Jing; Mark Raffeld; Susan Moir; Thomas A. Fleisher; Louis M. Staudt; Helen C. Su; Michael J. Lenardo
• Keywords: B-Lymphocytes; 0303 health sciences; Microscopy, Confocal; Base Sequence; Gene Expression Profiling; Immunoblotting; Molecular Sequence Data; Mutation, Missense; NF-kappa B; High-Throughput Nucleotide Sequencing; Enzyme-Linked Immunosorbent Assay; Lymphocytosis; Flow Cytometry; Article; Pedigree; 3. Good health; CARD Signaling Adaptor Proteins; 03 medical and health sciences; Guanylate Cyclase; Splenomegaly; Cluster Analysis; Humans; Genetic Predisposition to Disease; Germ-Line Mutation

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.