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A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings
ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part o...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289122/ https://www.ncbi.nlm.nih.gov/pubmed/34232960 http://dx.doi.org/10.1371/journal.pgen.1009639 |
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author | Li, Qifei Dibus, Michal Casey, Alicia Yee, Christina S. K. Vargas, Sara O. Luo, Shiyu Rosen, Samantha M. Madden, Jill A. Genetti, Casie A. Brabek, Jan Brownstein, Catherine A. Kazerounian, Shideh Raby, Benjamin A. Schmitz-Abe, Klaus Kennedy, John C. Fishman, Martha P. Mullen, Mary P. Taylor, Joan M. Rosel, Daniel Agrawal, Pankaj B. |
author_facet | Li, Qifei Dibus, Michal Casey, Alicia Yee, Christina S. K. Vargas, Sara O. Luo, Shiyu Rosen, Samantha M. Madden, Jill A. Genetti, Casie A. Brabek, Jan Brownstein, Catherine A. Kazerounian, Shideh Raby, Benjamin A. Schmitz-Abe, Klaus Kennedy, John C. Fishman, Martha P. Mullen, Mary P. Taylor, Joan M. Rosel, Daniel Agrawal, Pankaj B. |
author_sort | Li, Qifei |
collection | PubMed |
description | ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder. |
format | Online Article Text |
id | pubmed-8289122 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-82891222021-07-31 A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings Li, Qifei Dibus, Michal Casey, Alicia Yee, Christina S. K. Vargas, Sara O. Luo, Shiyu Rosen, Samantha M. Madden, Jill A. Genetti, Casie A. Brabek, Jan Brownstein, Catherine A. Kazerounian, Shideh Raby, Benjamin A. Schmitz-Abe, Klaus Kennedy, John C. Fishman, Martha P. Mullen, Mary P. Taylor, Joan M. Rosel, Daniel Agrawal, Pankaj B. PLoS Genet Research Article ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder. Public Library of Science 2021-07-07 /pmc/articles/PMC8289122/ /pubmed/34232960 http://dx.doi.org/10.1371/journal.pgen.1009639 Text en © 2021 Li et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Li, Qifei Dibus, Michal Casey, Alicia Yee, Christina S. K. Vargas, Sara O. Luo, Shiyu Rosen, Samantha M. Madden, Jill A. Genetti, Casie A. Brabek, Jan Brownstein, Catherine A. Kazerounian, Shideh Raby, Benjamin A. Schmitz-Abe, Klaus Kennedy, John C. Fishman, Martha P. Mullen, Mary P. Taylor, Joan M. Rosel, Daniel Agrawal, Pankaj B. A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings |
title | A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings |
title_full | A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings |
title_fullStr | A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings |
title_full_unstemmed | A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings |
title_short | A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings |
title_sort | homozygous stop-gain variant in arhgap42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289122/ https://www.ncbi.nlm.nih.gov/pubmed/34232960 http://dx.doi.org/10.1371/journal.pgen.1009639 |
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