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Heterozygous Mutations in IKAROS in Patients with Progressive Loss of B Cells and Hypogammaglobulinemia

Thursday, September 17, 2015 — Poster Session III

3:30 p.m. – 5:00 p.m.
FAES Terrace


  • HS Kuehn
  • JE Niemela
  • J Stoddard
  • S Ganesan
  • K Lemberg
  • J Monsale
  • S Rampertaap
  • A Agharahimi
  • A Hussey
  • TA Fleisher
  • SD Rosenzweig


Common variable immunodeficiency (CVID) is characterized by delayed onset of hypogammaglobulinemia that is not explained by previous exposures, treatment or infections. The genetic etiology is unknown in the majority of cases and only 10% of patients have a family history of disease. Most patients have normal numbers of B cells but lack plasma cells. The recent use of new genomic approaches, including whole exome sequencing (WES) has begun to reveal the genetic etiologies in several subsets of patients with poorly defined immunodeficiencies. Recently, we identified heterozygous mutations in the hematopoietic transcription factor IKAROS (IKZF1) in the CVID patients with low B cell numbers. This gene encodes a transcription factor that belongs to the family of zinc-finger (ZF) DNA-binding proteins associated with chromatin remodeling and can act to both enhance and repress gene transcription. The mutation was found in highly conserved ZF2 region, which is essential for DNA binding. Mutant proteins were analyzed for DNA binding using electrophoretic mobility shift assays (EMSA) and confocal microscopy. Both result demonstrated that mutant protein disrupted both DNA binding and pericenctomeric targeting. Here we presented heterozygous mutations in the transcription factor IKAROS cause an autosomal dominant form of CVID associated with a striking decrease in B cell numbers and serum immunoglobulins.

Category: Immunology