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Novel IRF2BP2 mutation linked to CVID–like immunodeficiency

Researchers identified a novel mutation in IRF2BP2 in a family with a history of common variable immunodeficiency disorder, which may be the cause of the disease phenotype, according to a study.

“We have described a novel mutation in IRF2BP2, which appears to affect B-cell maturation and might represent an autosomal dominant cause of common variable immunodeficiency disorder (CVID)-like immunodeficiency,” Michael D. Keller, MD, immunologist with the division of allergy and immunology at the Children’s National Medical Center in Washington, and colleagues wrote in their study. “Additional study of IRF2BP2 might yield further understanding of its importance in B-cell development.”

Keller and colleagues analyzed whole-exome sequencing on a family containing multiple members with a diagnosis of CVID, where the family members were screened with a support vector machine (SVM) algorithm used in a previous CVID study, according to the abstract. The researchers performed protein immunoblots, reverse transcription polymerase chain reaction (RT-PCR) and in vitro plasmablast differentiation assays on Epstein-Barr Virus (EBV) lymphoblastoids cell lines (LCLs) for both patient and control groups.

Among family members with CVID, Keller and colleagues found a heterozygous mutation c.1652G>A:p.(S551N) in IRF2BP2 that, when transducted into control human B cells, decreases in vitro production of plasmablasts, according to the abstract.

“Quantitative PCR of IRF2BP2 from the proband and control EBV-LCLs showed a higher expression level in the proband versus levels in the healthy control subjects,” Keller and colleagues wrote. “Comparative evaluation of transcript levels from isoform 1 versus isoform 2 (which differ in the length of exon 1) showed a uniform increase in the IRF2BP2 expression level in the proband.”

The researchers also found that the proband and other subjects were genetically dissimilar from polygenic CVID, according to the SVM algorithm.

“Analysis of the top 658 single nucleotide polymorphisms/copy number variations (SNPs/CNVs) by using the CVID SVM algorithm predicted that the proband in family 1 fell outside the region of polygenic CVID cases on the hyperplane,” the researchers wrote. “A similar analysis was performed for 6 subjects with several forms of monogenic immunodeficiency, resulting in CVID-like disease (LRBA, IL21, BAFFR, ICOS, and CD27 deficiency), as well as 3 patients with CVID and mutations in TACI, and all were similarly predicted to be genetically unique from polygenic patients with CVID.” – by Jeff Craven

Disclosure: The researchers report no relevant financial disclosures.