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

Undiagnosed Disease Network

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere686
JournalMolecular Genetics and Genomic Medicine
Volume7
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Fibroblast Growth Factors
Immunoglobulin G
Carrier Proteins
T-Lymphocytes
Genes
Nuclear Family
Cytotoxic T-Lymphocytes
Histocompatibility Testing
Proteins
DNA

Keywords

  • cytotoxic lymphocytes
  • heritable
  • IgG4-RD

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

IgG4-related disease : Association with a rare gene variant expressed in cytotoxic T cells. / Undiagnosed Disease Network.

In: Molecular Genetics and Genomic Medicine, Vol. 7, No. 6, e686, 01.06.2019.

Research output: Contribution to journalArticle

@article{a8ea8af80d8348ba96a14c5023957b2e,
title = "IgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cells",
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 = "cytotoxic lymphocytes, heritable, IgG4-RD",
author = "{Undiagnosed Disease Network} and Newman, {John H.} and Aaron Shaver and Sheehan, {Jonathan H.} and Simon Mallal and Stone, {John H.} and Shiv Pillai and Lisa Bastarache and Derek Riebau and Hugues Allard-Chamard and Stone, {William M.} and Cory Perugino and Mark Pilkinton and Smith, {Scott A.} and McDonnell, {Wyatt J.} and Capra, {John A.} and Jens Meiler and Joy Cogan and Kelly Xing and Mahajan, {Vinay S.} and Hamid Mattoo and Rizwan Hamid and Phillips, {John A.} and Adams, {David R.} and Aaron Aday and Alejandro, {Mercedes E.} and Patrick Allard and Ashley, {Euan A.} and Azamian, {Mahshid S.} and Bacino, {Carlos A.} and Ashok Balasubramanyam and Hayk Barseghyan and Batzli, {Gabriel F.} and Beggs, {Alan H.} and Babak Behnam and Bellen, {Hugo J.} and Bernstein, {Jonathan A.} and Anna Bican and Bick, {David P.} and Birch, {Camille L.} and Devon Bonner and Boone, {Braden E.} and Bostwick, {Bret L.} and Briere, {Lauren C.} and Brown, {Donna M.} and Matthew Brush and Burke, {Elizabeth A.} and Burrage, {Lindsay C.} and Butte, {Manish J.} and Shan Chen and David Koeller",
year = "2019",
month = "6",
day = "1",
doi = "10.1002/mgg3.686",
language = "English (US)",
volume = "7",
journal = "Molecular genetics & genomic medicine",
issn = "2324-9269",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - IgG4-related disease

T2 - Association with a rare gene variant expressed in cytotoxic T cells

AU - Undiagnosed Disease Network

AU - Newman, John H.

AU - Shaver, Aaron

AU - Sheehan, Jonathan H.

AU - Mallal, Simon

AU - Stone, John H.

AU - Pillai, Shiv

AU - Bastarache, Lisa

AU - Riebau, Derek

AU - Allard-Chamard, Hugues

AU - Stone, William M.

AU - Perugino, Cory

AU - Pilkinton, Mark

AU - Smith, Scott A.

AU - McDonnell, Wyatt J.

AU - Capra, John A.

AU - Meiler, Jens

AU - Cogan, Joy

AU - Xing, Kelly

AU - Mahajan, Vinay S.

AU - Mattoo, Hamid

AU - Hamid, Rizwan

AU - Phillips, John A.

AU - Adams, David R.

AU - Aday, Aaron

AU - Alejandro, Mercedes E.

AU - Allard, Patrick

AU - Ashley, Euan A.

AU - Azamian, Mahshid S.

AU - Bacino, Carlos A.

AU - Balasubramanyam, Ashok

AU - Barseghyan, Hayk

AU - Batzli, Gabriel F.

AU - Beggs, Alan H.

AU - Behnam, Babak

AU - Bellen, Hugo J.

AU - Bernstein, Jonathan A.

AU - Bican, Anna

AU - Bick, David P.

AU - Birch, Camille L.

AU - Bonner, Devon

AU - Boone, Braden E.

AU - Bostwick, Bret L.

AU - Briere, Lauren C.

AU - Brown, Donna M.

AU - Brush, Matthew

AU - Burke, Elizabeth A.

AU - Burrage, Lindsay C.

AU - Butte, Manish J.

AU - Chen, Shan

AU - Koeller, David

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

KW - cytotoxic lymphocytes

KW - heritable

KW - IgG4-RD

UR - http://www.scopus.com/inward/record.url?scp=85067307520&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067307520&partnerID=8YFLogxK

U2 - 10.1002/mgg3.686

DO - 10.1002/mgg3.686

M3 - Article

C2 - 30993913

AN - SCOPUS:85067307520

VL - 7

JO - Molecular genetics & genomic medicine

JF - Molecular genetics & genomic medicine

SN - 2324-9269

IS - 6

M1 - e686

ER -