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...
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Public Library of Science (PLoS)
2021
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oai:doaj.org-article:aa7ea0af68b8420487248727773f68192021-12-02T20:02:46ZA homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings.1553-73901553-740410.1371/journal.pgen.1009639https://doaj.org/article/aa7ea0af68b8420487248727773f68192021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009639https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404ARHGAP42 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.Qifei LiMichal DibusAlicia CaseyChristina S K YeeSara O VargasShiyu LuoSamantha M RosenJill A MaddenCasie A GenettiJan BrabekCatherine A BrownsteinShideh KazerounianBenjamin A RabyKlaus Schmitz-AbeJohn C KennedyMartha P FishmanMary P MullenJoan M TaylorDaniel RoselPankaj B AgrawalPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009639 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Qifei Li Michal Dibus Alicia Casey Christina S K Yee Sara O Vargas Shiyu Luo Samantha M Rosen Jill A Madden Casie A Genetti Jan Brabek Catherine A Brownstein Shideh Kazerounian Benjamin A Raby Klaus Schmitz-Abe John C Kennedy Martha P Fishman Mary P Mullen Joan M Taylor Daniel Rosel Pankaj B Agrawal A homozygous stop-gain variant in ARHGAP42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings. |
| 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 |
article |
| author |
Qifei Li Michal Dibus Alicia Casey Christina S K Yee Sara O Vargas Shiyu Luo Samantha M Rosen Jill A Madden Casie A Genetti Jan Brabek Catherine A Brownstein Shideh Kazerounian Benjamin A Raby Klaus Schmitz-Abe John C Kennedy Martha P Fishman Mary P Mullen Joan M Taylor Daniel Rosel Pankaj B Agrawal |
| author_facet |
Qifei Li Michal Dibus Alicia Casey Christina S K Yee Sara O Vargas Shiyu Luo Samantha M Rosen Jill A Madden Casie A Genetti Jan Brabek Catherine A Brownstein Shideh Kazerounian Benjamin A Raby Klaus Schmitz-Abe John C Kennedy Martha P Fishman Mary P Mullen Joan M Taylor Daniel Rosel Pankaj B Agrawal |
| author_sort |
Qifei Li |
| title |
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_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_sort |
homozygous stop-gain variant in arhgap42 is associated with childhood interstitial lung disease, systemic hypertension, and immunological findings. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/aa7ea0af68b8420487248727773f6819 |
| work_keys_str_mv |
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