Congenital B cell lymphocytosis explained by novel germline CARD11 mutations

Abstract

Germline mutations in CARD11 that result in constitutive NF-κB activation and selective B cell expansion underlie congenital B cell lymphocytosis.

Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

“…31,32 This spontaneous complex formation was correlated previously with constitutive, receptorindependent, NF-kB activation. Here, we analyzed the subcellular distribution of DDK-CARD11 proteins by immunofluorescence after transfection into HEK 293 cells.…”

Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjögren’s syndrome

“…Interestingly, it has been recently demonstrated that germline gain of function mutations of CARD11, involved in NF-kB activation in both B and T cells, could induce lymphoproliferation restricted to B cells. 22 Alternatively, the genetic events allowing clonal B cells to escape may occur within the B cells themselves. Autoimmune B cells subjected to perpetual stimulation are more sensitive to the presence of additional mutations leading to clonal selection.…”

Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

“…Some gain-of-function (GOF) CARD11 alleles have been associated with B-cell lymphoproliferation, 29,30 and a GOF effect could in principle explain the lymphoproliferative features of OS in P1. To study the impact of the second-site mutation on the cellular behavior of lymphocytes, we made use of a murine model that has previously been established to evaluate human CARD11 GOF mutations.…”

“…The functional reversion resulted in reconstitution of protein expression with partial reconstitution of NF-kB phosphorylation and subsequent transcriptional activity. Mutations in the coiledcoil domain of CARD11 have been associated with congenital B-cell lymphoproliferation 29 and B-cell lymphoma. 30 However, we documented that the p.Cys150Leu mutation did not elicit increased spontaneous or induced NF-kB signaling, and our murine experiments 25 render it unlikely that it conferred autonomous proliferative activity to patient T cells.…”