학술논문
IgG4‐related disease: Association with a rare gene variant expressed in cytotoxic T cells
Document Type
article
Author
Newman, John H; Shaver, Aaron; Sheehan, Jonathan H; Mallal, Simon; Stone, John H; Pillai, Shiv; Bastarache, Lisa; Riebau, Derek; Allard‐Chamard, Hugues; Stone, William M; Perugino, Cory; Pilkinton, Mark; Smith, Scott A; McDonnell, Wyatt J; Capra, John A; Meiler, Jens; Cogan, Joy; Xing, Kelly; Mahajan, Vinay S; Mattoo, Hamid; Hamid, Rizwan; Phillips, John A; Adams, David R; Aday, Aaron; Alejandro, Mercedes E; Allard, Patrick; Ashley, Euan A; Azamian, Mahshid S; Bacino, Carlos A; Balasubramanyam, Ashok; Barseghyan, Hayk; Batzli, Gabriel F; Beggs, Alan H; Behnam, Babak; Bellen, Hugo J; Bernstein, Jonathan A; Bican, Anna; Bick, David P; Birch, Camille L; Bonner, Devon; Boone, Braden E; Bostwick, Bret L; Briere, Lauren C; Brown, Donna M; Brush, Matthew; Burke, Elizabeth A; Burrage, Lindsay C; Butte, Manish J; Chen, Shan; Clark, Gary D; Coakley, Terra R; Cooper, Cynthia M; Cope, Heidi; Craigen, William J; D'Souza, Precilla; Davids, Mariska; Davidson, Jean M; Dayal, Jyoti G; Dell'Angelica, Esteban C; Dhar, Shweta U; Dipple, Katrina M; Donnell‐Fink, Laurel A; Dorrani, Naghmeh; Dorset, Daniel C; Douine, Emilie D; Draper, David D; Dries, Annika M; Eckstein, David J; Emrick, Lisa T; Eng, Christine M; Enns, Gregory M; Eskin, Ascia; Esteves, Cecilia; Estwick, Tyra; Fernandez, Liliana; Ferreira, Carlos; Fisher, Paul G; Fogel, Brent L; Friedman, Noah D; Gahl, William A; Glanton, Emily; Godfrey, Rena A; Goldman, Alica M; Goldstein, David B; Gould, Sarah E; Gourdine, Jean‐Philippe F; Groden, Catherine A; Gropman, Andrea L; Haendel, Melissa; Hanchard, Neil A; Handley, Lori H; Herzog, Matthew R; High, Francis; Holm, Ingrid A; Hom, Jason; Howerton, Ellen M; Huang, Yong; Jamal, Fariha; Jiang, Yong‐hui; Johnston, Jean M
Source
Molecular Genetics & Genomic Medicine. 7(6)
Subject
Language
Abstract
BackgroundFamily 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 ~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.