Abstract
Purpose: Activating germline mutations in CARD11 have recently been linked to a rare genetic disorder associated with congenital B cell lymphocytosis. We describe a patient with a similar clinical phenotype who had a de novo germline G123D CARD11 mutation.
Methods: Whole exome sequencing was performed on DNA from the patient and his biological parents. Laboratory studies examined characteristics of the patient’s B and T lymphocytes. A CARD11 cDNA containing the mutation was transfected into a lymphocyte cell line to gain an understanding of its function. RNA sequencing was performed on samples from the patient and from patients with alternate germline CARD11 mutations and differential gene expression analysis was performed.
Results: The patient had a decade-long history of severe polyclonal B lymphocytosis in the 20,000–90,000 lymphocytes/mm3range, which was markedly exacerbated by EBV infection and splenectomy at different times. He had a heterozygous germline CARD11 mutation causing a G123D amino acid substitution, which was demonstrated to induce NF-κB activation in unstimulated lymphocytes. In contrast to previous patients with CARD11 mutations, this patient’s B cells exhibited higher expression of several cell cycle progression genes, as well as enhanced proliferation and improved survival following B cell receptor stimulation.
Conclusions: This is the third reported germline and first de novo CARD11 mutation shown to cause congenital B cell lymphocytosis. The mutation was associated with a dramatically greater lymphocytosis than in previously described cases, disproportionate to the level of constitutive NF-κB activation. However, comparative review of the patient’s clinical history, combined with additional genomic and functional analyses, underscore other important variables that may affect pathophysiology or regulate mutant CARD11 function in B cell proliferation and disease. We now refer to these patients as having BENTA disease (B cell Expansion with NF-κB and T cell Anergy).
| Original language | English |
|---|---|
| Pages (from-to) | 32-46 |
| Number of pages | 15 |
| Journal | Journal of Clinical Immunology |
| Volume | 35 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 27 2015 |
Bibliographical note
Funding Information:We thank the patient and their family for participating in this study. We also thank Dr. Koneti Rao for clinical consultation and Ms. Shakuntala Guprasad for flow cytometry support. This work was supported in part by the Intramural Research Program of the National Institutes of Health, the National Institute for Allergy and Infectious Diseases, and the National Cancer Institute. The authors also acknowledge support from the Concern Foundation and an intramural grant from Uniformed Services University of the Health Sciences (to A.L. Snow), and from DanceBlue, a student-run effort at the University of Kentucky to support pediatric oncology clinical care and research.
Publisher Copyright:
© 2014, Springer Science+Business Media New York (outside the USA).
Keywords
- B-cell lymphocytosis
- BENTA
- CARD11
- NF-κB
- congenital
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology