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Case Reports
. 2019 Jun;7(6):e686.
doi: 10.1002/mgg3.686. Epub 2019 Apr 16.

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

John H Newman  1 , Aaron Shaver  2 , Jonathan H Sheehan  3 , Simon Mallal  4 , John H Stone  5 , Shiv Pillai  6 , Lisa Bastarache  7 , Derek Riebau  8 , Hugues Allard-Chamard  6 , William M Stone  6 , Cory Perugino  6 , Mark Pilkinton  4 , Scott A Smith  4 , Wyatt J McDonnell  4 , John A Capra  3 , Jens Meiler  3 , Joy Cogan  1   9 , Kelly Xing  6 , Vinay S Mahajan  6 , Hamid Mattoo  6 , Rizwan Hamid  1   9 , John A Phillips 3rd  1   9 ; Undiagnosed Disease Network
Collaborators, Affiliations
Case Reports

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

John H Newman et al. Mol Genet Genomic Med. 2019 Jun.

Abstract

Background: Family 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.

Methods: We 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.

Results: The 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 ~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.

Conclusions: The 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.

Keywords: IgG4-RD; cytotoxic lymphocytes; heritable.

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Conflict of interest statement

None declared.

Figures

Figure 1
Figure 1
A structural model for FGFBP2The model for FGFBP2 suggests a mechanism for the effect of the frameshift variant. (a) The C‐terminal domain is predicted to form two alpha helices held at an angle by a conserved disulfide bond. Protein backbone is shown as green ribbons; sidechains are shown as sticks; position of frameshift is highlighted in red. (b) The frameshifted sequence is predicted to form a disordered random coil
Figure 2
Figure 2
Subjects with the FGFBP2 c.268C>T p.Pro90Ser variant have increased numbers of circulating plasmablasts, effector CD4 + T cells, and CD4 + CTLs. Gating strategy for enumeration of circulating plasmablasts (a) and CD45RO+ CD27‐ effector CD4 + T cells and CD4 + CTLs (b). The three subjects (father and two sons) presented with evidence for lymphocyte activation in both B and T cell compartments. They had relatively high proportions of circulating plasmablasts (a) as well as of antigen‐experienced effector CD4 + T cells and CD4 + CTLs (b) when compared with three healthy controls
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