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Researchers Classify New Common Variable Immunodeficiency Disorder, Link to Genetic Cause

NEW YORK (GenomeWeb) – An international team of researchers has published a study describing a new subtype of common variable immunodeficiency disorder (CVID) resulting from a mutation in IKAROS, a protein that plays a central role in the development of immune cells.

The University of Utah School of Medicine's Harry Hill had been regularly seeing a small number of patients with continual sinus infections and pneumonia that were getting worse, despite treatment. He suspected a kind of CVID was to blame, but the patients he saw — some of whom were related to each other — didn't have the genetic problems associated with CVID subtypes that have already been described. According to the University of Utah, Hill conferred with his colleagues, molecular pathologists Attila Kumánovics and Karl Voelkerding, to see if they could find a genetic cause to these patients' problems.

Meanwhile, the university said, Rockefeller University's Mary Ellen Conley had been seeing patients of her own with similar problems, and decided to collaborate with the Utah researchers. Together with more than two dozen other researchers in the US and Europe, the team found a total of six unrelated families who shared similar symptoms.

As the team reported today in the New England Journal of Medicine, the patients being studied had a low number of B cells, which is not common with other forms of CVID. The researchers used whole-exome sequencing and array-based comparative genomic hybridization to evaluate these patients with CVID and low B-cell numbers. They used an electrophoretic mobility-shift assay and confocal microscopy to analyze mutant proteins for DNA binding, and flow cytometry to analyze peripheral-blood lymphocytes and bone marrow aspirates.

In all, they found six different heterozygous mutations in IKZF1 — a gene encoding the transcription factor IKAROS —in 29 people 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 authors wrote in their paper. "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."

The researchers also found that members of these families showed progressive loss of B cells and serum immunoglobulins. The bone marrow aspirates of two patients showed markedly decreased early B-cell precursors, and acute lymphoblastic leukemia developed in two of the 29.

"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," the authors wrote. They believe this new classification will help patients afflicted with this subtype of CVID get the precise treatments that will help them.