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Title: IGSF3 mutation identified in patient with severe COPD alters cell function and motility
Authors: Kelly S. Schweitzer
Natini Jinawath
Raluca Yonescu
Kevin Ni
Natalia Rush
Varodom Charoensawan
Irina Bronova
Evgeny Berdyshev
Sonia M. Leach
Lucas A. Gillenwater
Russel P. Bowler
David B. Pearse
Constance A. Griffin
Irina Petrache
National Jewish Health
Indiana University-Purdue University Indianapolis
Mahidol University
Johns Hopkins Medical Institutions
Faculty of Medicine Ramathibodi Hospital
Keywords: Medicine
Issue Date: 23-Jul-2020
Citation: JCI insight. Vol.5, No.14 (2020)
Abstract: Cigarette smoking (CS) and genetic susceptibility determine the risk for development, progression, and severity of chronic obstructive pulmonary diseases (COPD). We posited that an incidental balanced reciprocal chromosomal translocation was linked to a patient's risk of severe COPD. We determined that 46,XX,t(1;4)(p13.1;q34.3) caused a breakpoint in the immunoglobulin superfamily member 3 (IGSF3) gene, with markedly decreased expression. Examination of COPDGene cohort identified 14 IGSF3 SNPs, of which rs1414272 and rs12066192 were directly and rs6703791 inversely associated with COPD severity, including COPD exacerbations. We confirmed that IGSF3 is a tetraspanin-interacting protein that colocalized with CD9 and integrin B1 in tetraspanin-enriched domains. IGSF3-deficient patient-derived lymphoblastoids exhibited multiple alterations in gene expression, especially in the unfolded protein response and ceramide pathways. IGSF3-deficient lymphoblastoids had high ceramide and sphingosine-1 phosphate but low glycosphingolipids and ganglioside levels, and they were less apoptotic and more adherent, with marked changes in multiple TNFRSF molecules. Similarly, IGSF3 knockdown increased ceramide in lung structural cells, rendering them more adherent, with impaired wound repair and weakened barrier function. These findings suggest that, by maintaining sphingolipid and membrane receptor homeostasis, IGSF3 is required for cell mobility-mediated lung injury repair. IGSF3 deficiency may increase susceptibility to CS-induced lung injury in COPD.
ISSN: 23793708
Appears in Collections:Scopus 2020

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