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IgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cells

dc.contributor.authorNewman, John H.
dc.contributor.authorShaver, Aaron
dc.contributor.authorSheehan, Jonathan H.
dc.contributor.authorMallal, Simon
dc.contributor.authorBastarache, Lisa
dc.contributor.authorRiebau, Derek
dc.contributor.authorPilkinton, Mark
dc.contributor.authorSmith, Scott A.
dc.contributor.authorMcDonnell, Wyatt J.
dc.contributor.authorCapra, John A.
dc.contributor.authorMeiler, Jens
dc.contributor.authorCogan, Joy
dc.contributor.authorHamid, Rizwan
dc.contributor.authorPhillips, John A., III
dc.identifier.citationNewman JH, Shaver A, Sheehan JH, et al. IgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cells. Mol Genet Genomic Med. 2019;7(6):e686. doi:10.1002/mgg3.686en_US
dc.descriptionOnly Vanderbilt University affiliated authors are listed on VUIR. For a full list of authors, version of record aten_US
dc.description.abstractBackgroundFamily screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons. MethodsWe performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2. ResultsThe three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4+T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in similar to 40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD. ConclusionsThe presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease.en_US
dc.description.sponsorshipThis work was supported by NIH/NHGRI 5 U01 HG 007674-05 (Phillips, Newman, Hamid and Cogan) 07/01/14 - 03/31/18. Vanderbilt Center for Undiagnosed Diseases (VCUD); NIH CTSA Grant (RR024975-01/TR000445-06); NIH/NIAID U19 AI110495 (Pillai); NIH AI113163 (Mahajan); NIH T32AR007258 (Perugino).en_US
dc.publisherMolecular Genetrics & Genome Medicineen_US
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.subjectcytotoxic lymphocytesen_US
dc.titleIgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cellsen_US

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