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IGSF3 mutation identified in patient with severe COPD alters cell function and motility
Kelly S. Schweitzer, … , Constance A. Griffin, Irina Petrache
Kelly S. Schweitzer, … , Constance A. Griffin, Irina Petrache
Published June 23, 2020
Citation Information: JCI Insight. 2020;5(14):e138101. https://doi.org/10.1172/jci.insight.138101.
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Research Article Cell biology Pulmonology

IGSF3 mutation identified in patient with severe COPD alters cell function and motility

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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.

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

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Figure 1

IGSF3 disruption from a balanced translocation in a patient with severe emphysema.

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IGSF3 disruption from a balanced translocation in a patient with severe...
(A and B) Complete karyotype in a lymphoblastoid cell line generated from patients’ lymphocytes showing a balanced translocation (B, arrows) between G-banded chromosomes 1 and 4: t(1;4)(p13.1;q34.3). der(1), derivative chromosome 1; der(4), derivative chromosome 4. (C–F) Metaphase FISH analysis of the translocation breakpoint. (C) BAC clones CTD-2329H4 and CTC-779C7on chromosome 1p13.1 show intact signals. (D) BAC clone RP4-686J16 on chromosome 1p13.1 shows green split signals between der(1) and der(4). (E) BAC clone RP11-763N18 on chromosome 4q34.3 shows the split signals of der(1) and der(4) (green), while those of RP11-495H13 (chromosome 4q34.3; orange) are intact. (F) DNA fiber FISH analysis demonstrating the translocation breakpoint within BAC clones RP4-686J16 (chromosome 1p13.1; green) and RP11-763N18 (chromosome 4q34.3; orange). (G) Schematic illustrating the translocation breakpoint regions on chromosomes 1p and 4q. Genomic locations shown are based on the UCSC genome browser (hg38). (H and I) Expression levels of IGSF3 mRNA measured by qPCR targeted array (n = 6 independent experiments, normalized to 18S, H) and of IGSF3 protein detected by immunoblotting (I, β-actin was loading control) in transformed lymphoblastoid cells derived from patient lymphocytes compared with lymphoblastoids derived from healthy donor lymphocytes (control). ****P < 0.0001 vs. control, Student’s t test.

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