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Congenital B cell lymphocytosis explained by novel germline CARD11 mutations.

Authors: Snow, AL  Xiao, W  Stinson, JR  Lu, W  Chaigne-Delalande, B  Zheng, L  Pittaluga, S  Matthews, HF  Schmitz, R  Jhavar, S  Kuchen, S  Kardava, L  Wang, W  Lamborn, IT  Jing, H  Raffeld, M  Moir, S  Fleisher, TA  Staudt, LM  Su, HC  Lenardo, MJ 
Citation: Snow AL, etal., J Exp Med. 2012 Nov 19;209(12):2247-61. doi: 10.1084/jem.20120831. Epub 2012 Nov 5.
Pubmed: (View Article at PubMed) PMID:23129749
DOI: Full-text: DOI:10.1084/jem.20120831

Nuclear factor-kappaB (NF-kappaB) controls genes involved in normal lymphocyte functions, but constitutive NF-kappaB 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-kappaB 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-kappaB 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.


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CRRD Object Information
CRRD ID: 11100033
Created: 2016-06-14
Species: All species
Last Modified: 2016-06-14
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.