[HTML][HTML] Loss of B cells in patients with heterozygous mutations in IKAROS

HS Kuehn, B Boisson… - … England Journal of …, 2016 - Mass Medical Soc
HS Kuehn, B Boisson, C Cunningham-Rundles, J Reichenbach, A Stray-Pedersen…
New England Journal of Medicine, 2016Mass Medical Soc
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 …
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.)
The New England Journal Of Medicine