COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.

TitleCOPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.
Publication TypeJournal Article
Year of Publication2015
AuthorsWatkin, LB, Jessen, B, Wiszniewski, W, Vece, TJ, Jan, M, Sha, Y, Thamsen, M, Santos-Cortez, RLP, Lee, K, Gambin, T, Forbes, LR, Law, CS, Stray-Pedersen, A, Cheng, MH, Mace, EM, Anderson, MS, Liu, D, Tang, LFung, Nicholas, SK, Nahmod, K, Makedonas, G, Canter, DL, Kwok, P-Y, Hicks, J, Jones, KD, Penney, S, Jhangiani, SN, Rosenblum, MD, Dell, SD, Waterfield, MR, Papa, FR, Muzny, DM, Zaitlen, N, Leal, SM, Gonzaga-Jauregui, C, Boerwinkle, E, N Eissa, T, Gibbs, RA, Lupski, JR, Orange, JS, Shum, AK
Corporate Authors
JournalNat Genet
Volume47
Issue6
Pagination654-60
Date Published2015 Jun
ISSN1546-1718
KeywordsAmino Acid Sequence, Arthritis, Autoimmune Diseases, Child, Preschool, Coatomer Protein, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Genetic Association Studies, Genetic Predisposition to Disease, Golgi Apparatus, HEK293 Cells, Humans, Infant, Lod Score, Lung Diseases, Interstitial, Male, Molecular Sequence Data, Pedigree, Protein Transport
Abstract

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.

DOI10.1038/ng.3279
Alternate JournalNat. Genet.
PubMed ID25894502
PubMed Central IDPMC4513663
Grant ListU54HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
L30 HL098006 / HL / NHLBI NIH HHS / United States
R01AI067946 / AI / NIAID NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
R01 HL122533 / HL / NHLBI NIH HHS / United States
R01 AI067946 / AI / NIAID NIH HHS / United States
K23 NS078056 / NS / NINDS NIH HHS / United States
T32 AI053831 / AI / NIAID NIH HHS / United States
AI053831 / AI / NIAID NIH HHS / United States
K08 AR062064 / AR / NIAMS NIH HHS / United States
2R01NS058529 / NS / NINDS NIH HHS / United States
K08HL095659 / HL / NHLBI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
K25 HL121295 / HL / NHLBI NIH HHS / United States
K23NS078056 / NS / NINDS NIH HHS / United States
K08 HL095659 / HL / NHLBI NIH HHS / United States