Congenital B cell lymphocytosis explained by novel germline CARD11 mutations.
J Exp Med
; 209(12): 2247-61, 2012 Nov 19.
Article
en En
| MEDLINE
| ID: mdl-23129749
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfocitos B
/
Predisposición Genética a la Enfermedad
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Proteínas Adaptadoras de Señalización CARD
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Guanilato Ciclasa
/
Linfocitosis
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Exp Med
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos