Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder

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• 作者：Michael D. Keller ; MD^a ; ^&lowast ; ; Rahul Pandey ; PhD^b ; ^&lowast ; ; Dong Li ; PhD^b ; ^&lowast ; ; Joseph Glessner ; PhD^b ; ^&Dagger ; ; Lifeng Tian ; PhD^b ; ^&Dagger ; ; Sarah E. Henrickson ; MD ; PhD^c ; Ivan K. Chinn ; MD^d ; ^e ; Linda Monaco-Shawver ; BSc^b ; ^c ; Jennifer Heimall ; MD^c ; Cuiping Hou ; BSc^b ; Frederick G. Otieno ; MS^b ; Soma Jyonouchi ; MD^c ; Leonard Calabrese ; DO^f ; Joris van Montfrans ; MD^g ; Jordan S. Orange ; MD ; PhD^d ; ^§ ; ; ^{orange@bcm.edu" class="auth_mail" title="E-mail the corresponding author} ; Hakon Hakonarson ; MD ; PhD^b ; ^§ ; ; ^{hakonarson@email.chop.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Common variable immunodeficiency ; machine learning ; primary antibody deficiency ; IRF2BP2 ; immunoglobulin
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：138
• 期：2
• 页码：544-550.e4
• 全文大小：2068 K

文摘

Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint.

Objective

We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders.

Methods

A family with multiple members with a diagnosis of CVID was screened by using whole-exome sequencing. The proband and other subjects with mutations associated with CVID-like phenotypes were screened through the SVM algorithm from our recent CVID genome-wide association study. RT-PCR, protein immunoblots, and in vitro plasmablast differentiation assays were performed on patient and control EBV lymphoblastoids cell lines.

Results

Exome sequencing identified a novel heterozygous mutation in IRF2BP2 (c.1652G>A:p.[S551N]) in affected family members. Transduction of the mutant gene into control human B cells decreased production of plasmablasts in vitro, and IRF2BP2 transcripts and protein expression were increased in proband versus control EBV-immortalized lymphoblastoid cell lines. The SVM algorithm categorized the proband and subjects with other immunodeficiency-associated gene variants in TACI, BAFFR, ICOS, CD21, LRBA, and CD27 as genetically dissimilar from polygenic CVID.

Conclusion

A novel IRFBP2 mutation was identified in a family with autosomal dominant CVID. Transduction experiments suggest that the mutant protein has an effect on B-cell differentiation and is likely a monogenic cause of the family's CVID phenotype. Successful grouping by the SVM algorithm suggests that our family and other subjects with rare immunodeficiency disorders cluster separately and lack the genetic pattern present in polygenic CVID cases.