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Loss of B Cells in Patients with Heterozygous Mutations in IKAROS

N Engl J Med. 2016 Mar 17;374(11):1032-1043. doi: 10.1056/NEJMoa1512234.

Abstract

Background: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells.

Methods: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates.

Results: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients.

Conclusions: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antigens, CD / analysis
  • B-Lymphocytes*
  • Bone Marrow / immunology
  • Bone Marrow Examination
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 7
  • Common Variable Immunodeficiency / genetics*
  • Common Variable Immunodeficiency / immunology
  • Exome
  • Female
  • Heterozygote
  • Humans
  • Ikaros Transcription Factor / genetics*
  • Immunoglobulin G / blood
  • Lymphocyte Count
  • Male
  • Mutation*
  • Pedigree
  • Sequence Analysis, DNA / methods

Substances

  • Antigens, CD
  • IKZF1 protein, human
  • Immunoglobulin G
  • Ikaros Transcription Factor