Congenital B cell lymphocytosis explained by novel germline CARD11 mutations

Andrew L. Snow*, Wenming Xiao, Jeffrey R. Stinson, Wei Lu, Chaigne Delalande Benjamin, 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. SuMichael J. Lenardo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

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 induceB cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.

Original languageEnglish
Pages (from-to)2247-2261
Number of pages15
JournalJournal of Experimental Medicine
Volume209
Issue number12
DOIs
StatePublished - Nov 2012
Externally publishedYes

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