IgG4‐related disease: Association with a rare gene variant expressed in cytotoxic T cells. Issue 6 (16th April 2019)

• Record Type: Journal Article
• Authors: 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.
• Other Names: Adams David R. investigator.; Aday Aaron investigator.; Alejandro Mercedes E. investigator.; Allard Patrick investigator.; Ashley Euan A. investigator.; Azamian Mahshid S. investigator.; Bacino Carlos A. investigator.; Balasubramanyam Ashok investigator.; Barseghyan Hayk investigator.; Batzli Gabriel F. investigator.; Beggs Alan H. investigator.; Behnam Babak investigator.; Bellen Hugo J. investigator.; Bernstein Jonathan A. investigator.; Bican Anna investigator.; Bick David P. investigator.; Birch Camille L. investigator.; Bonner Devon investigator.; Boone Braden E. investigator.; Bostwick Bret L. investigator.; Briere Lauren C. investigator.; Brown Donna M. investigator.; Brush Matthew investigator.; Burke Elizabeth A. investigator.; Burrage Lindsay C. investigator.; Butte Manish J. investigator.; Chen Shan investigator.; Clark Gary D. investigator.; Coakley Terra R. investigator.; Cooper Cynthia M. investigator.; Cope Heidi investigator.; Craigen William J. investigator.; D'Souza Precilla investigator.; Davids Mariska investigator.; Davidson Jean M. investigator.; Dayal Jyoti G. investigator.; Dell'Angelica Esteban C. investigator.; Dhar Shweta U. investigator.; Dipple Katrina M. investigator.; Donnell‐Fink Laurel A. investigator.; Dorrani Naghmeh investigator.; Dorset Daniel C. investigator.; Douine Emilie D. investigator.; Draper David D. investigator.; Dries Annika M. investigator.; Eckstein David J. investigator.; Emrick Lisa T. investigator.; Eng Christine M. investigator.; Enns Gregory M. investigator.; Eskin Ascia investigator.; Esteves Cecilia investigator.; Estwick Tyra investigator.; Fernandez Liliana investigator.; Ferreira Carlos investigator.; Fisher Paul G. investigator.; Fogel Brent L. investigator.; Friedman Noah D. investigator.; Gahl William A. investigator.; Glanton Emily investigator.; Godfrey Rena A. investigator.; Goldman Alica M. investigator.; Goldstein David B. investigator.; Gould Sarah E. investigator.; Gourdine Jean‐Philippe F. investigator.; Groden Catherine A. investigator.; Gropman Andrea L. investigator.; Haendel Melissa investigator.; Hanchard Neil A. investigator.; Handley Lori H. investigator.; Herzog Matthew R. investigator.; High Francis investigator.; Holm Ingrid A. investigator.; Hom Jason investigator.; Howerton Ellen M. investigator.; Huang Yong investigator.; Jamal Fariha investigator.; Jiang Yong‐hui investigator.; Johnston Jean M. investigator.; Jones Angela L. investigator.; Karaviti Lefkothea investigator.; Koeller David M. investigator.; Kohane Isaac S. investigator.; Kohler Jennefer N. investigator.; Krasnewich Donna M. investigator.; Korrick Susan investigator.; Krieg Elizabeth L. investigator.; Krier Joel B. investigator.; Kyle Jennifer E. investigator.; Lalani Seema R. investigator.; Christopher Lau C. investigator.; Lazar Jozef investigator.; LeBlanc Kimberly investigator.; Lee Brendan H. investigator.; Lee Hane investigator.; Levy Shawn E. investigator.; Lewis Richard A. investigator.; Lincoln Sharyn A. investigator.; Loo Sandra K. investigator.; Loscalzo Joseph investigator.; Maas Richard L. investigator.; Macnamara Ellen F. investigator.; MacRae Calum A. investigator.; Maduro Valerie V. investigator.; Majcherska Marta M. investigator.; Malicdan May Christine V. investigator.; Mamounas Laura A. investigator.; Manolio Teri A. investigator.; Markello Thomas C. investigator.; Marom Ronit investigator.; Martin Martin G. investigator.; Martínez‐Agosto Julian A. investigator.; Marwaha Shruti investigator.; May Thomas investigator.; McConkie‐Rosell Allyn investigator.; McCormack Colleen E. investigator.; McCray Alexa T. investigator.; Merker Jason D. investigator.; Metz Thomas O. investigator.; Might Matthew investigator.; Moretti Paolo M. investigator.; Morimoto Marie investigator.; Mulvihill John J. investigator.; Murdock David R. investigator.; Murphy Jennifer L. investigator.; Muzny Donna M. investigator.; Nehrebecky Michele E. investigator.; Nelson Stan F. investigator.; Scott Newberry J. investigator.; Nicholas Sarah K. investigator.; Novacic Donna investigator.; Orange Jordan S. investigator.; Orengo James P. investigator.; Carl Pallais J. investigator.; Palme Christina G. S. investigator.; Papp Jeanette C. investigator.; Parker Neil H. investigator.; Pena Loren D. M. investigator.; Posey Jennifer E. investigator.; Postlethwait John H. investigator.; Potocki Lorraine investigator.; Pusey Barbara N. investigator.; Reuter Chloe M. investigator.; Robertson Amy K. investigator.; Rodan Lance H. investigator.; Rosenfeld Jill A. investigator.; Sampson Jacinda B. investigator.; Samson Susan L. investigator.; Schoch Kelly investigator.; Schroeder Molly C. investigator.; Scott Daryl A. investigator.; Sharma Prashant investigator.; Shashi Vandana investigator.; Silverman Edwin K. investigator.; Sinsheimer Janet S. investigator.; Smith Kevin S. investigator.; Spillmann Rebecca C. investigator.; Stoler Joan M. investigator.; Stong Nicholas investigator.; Sullivan Jennifer A. investigator.; Sweetser David A. investigator.; Tan Queenie K.‐G. investigator.; Tifft Cynthia J. investigator.; Toro Camilo investigator.; Tran Alyssa A. investigator.; Urv Tiina K. investigator.; Valivullah Zaheer M. investigator.; Vilain Eric investigator.; Vogel Tiphanie P. investigator.; Waggott Daryl M. investigator.; Wahl Colleen E. investigator.; Walley Nicole M. investigator.; Walsh Chris A. investigator.; Walker Melissa investigator.; Wan Jijun investigator.; Wangler Michael F. investigator.; Ward Patricia A. investigator.; Waters Katrina M. investigator.; Webb‐Robertson Bobbie‐Jo M. investigator.; Westerfield Monte investigator.; Wheeler Matthew T. investigator.; Wise Anastasia L. investigator.; Wolfe Lynne A. investigator.; Worthey Elizabeth A. investigator.; Yamamoto Shinya investigator.; Yang Yaping investigator.; Yoon Amanda J. investigator.; Yu Guoyun investigator.; Zastrow Diane B. investigator.; Zhao Chunli investigator.; Zheng Allison investigator.;
• Is Part Of: Molecular genetics & genomic medicine. Volume 7:Issue 6(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-04-16
• Subjects: cytotoxic lymphocytes -- heritable -- IgG4‐RD; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.686
• Languages: English
• ISSNs: 2324-9269

Abstract

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. Abstract : A rare cytotoxic T cell gene mutation in a protein that binds fibroblast growth factor has been found in a family where the proband father has known IgG4‐RD and two sons have elevated IgG4 and activated plasmablasts.