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A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations
Two daughters in a Chinese consanguineous family were diagnosed as diffuse pulmonary arteriovenous malformations (PAVMs) and screened using whole exome sequencing (WES) and copy number variations (CNVs) chips. Though no mutation was found in the established causative genes of capillary malformation-...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356835/ https://www.ncbi.nlm.nih.gov/pubmed/27835862 http://dx.doi.org/10.18632/oncotarget.13156 |
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author | Liu, Hong-zhou Du, Chun-xian Luo, Jing Qiu, Xue-ping Li, Zu-hua Lou, Qi-yong Yin, Zhan Zheng, Fang |
author_facet | Liu, Hong-zhou Du, Chun-xian Luo, Jing Qiu, Xue-ping Li, Zu-hua Lou, Qi-yong Yin, Zhan Zheng, Fang |
author_sort | Liu, Hong-zhou |
collection | PubMed |
description | Two daughters in a Chinese consanguineous family were diagnosed as diffuse pulmonary arteriovenous malformations (PAVMs) and screened using whole exome sequencing (WES) and copy number variations (CNVs) chips. Though no mutation was found in the established causative genes of capillary malformation-AVMs (CM-AVMs) or PAVMs, Ser161Ile (hg19 NM_022493 c.482G>T) mutation in nuclear prelamin A recognition factor-like (NARFL) was identified. Ser161Ile mutation in NARFL conservation region was predicted to be deleterious and absent in 500 population controls and Exome Aggregation Consortium (ExAC) Database. And there was a dosage effect of the mutation on mRNA levels among family members and population controls, consistent with the instability of mutant mRNA in vitro. Accordingly, in lung tissue of the proband, NARFL protein expression was reduced but Fe(3+) was overloaded with vascular endothelial growth factor (VEGF) overexpression. Furthermore, NARFL-knockdown cell lines demonstrated decreased activity of cytosolic aconitase, while NARFL-knockout zebrafish presented ectopic subintestinal vessels sprouts and upregulated VEGF. So we concluded that the Ser161Ile mutant induced NARFL deficiency and eventually diffuse PAVMs probably through VEGF pathway. In a word, we detected a functional mutation in NARFL, which might be the pathogenic gene in this pedigree. |
format | Online Article Text |
id | pubmed-5356835 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53568352017-04-20 A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations Liu, Hong-zhou Du, Chun-xian Luo, Jing Qiu, Xue-ping Li, Zu-hua Lou, Qi-yong Yin, Zhan Zheng, Fang Oncotarget Research Paper Two daughters in a Chinese consanguineous family were diagnosed as diffuse pulmonary arteriovenous malformations (PAVMs) and screened using whole exome sequencing (WES) and copy number variations (CNVs) chips. Though no mutation was found in the established causative genes of capillary malformation-AVMs (CM-AVMs) or PAVMs, Ser161Ile (hg19 NM_022493 c.482G>T) mutation in nuclear prelamin A recognition factor-like (NARFL) was identified. Ser161Ile mutation in NARFL conservation region was predicted to be deleterious and absent in 500 population controls and Exome Aggregation Consortium (ExAC) Database. And there was a dosage effect of the mutation on mRNA levels among family members and population controls, consistent with the instability of mutant mRNA in vitro. Accordingly, in lung tissue of the proband, NARFL protein expression was reduced but Fe(3+) was overloaded with vascular endothelial growth factor (VEGF) overexpression. Furthermore, NARFL-knockdown cell lines demonstrated decreased activity of cytosolic aconitase, while NARFL-knockout zebrafish presented ectopic subintestinal vessels sprouts and upregulated VEGF. So we concluded that the Ser161Ile mutant induced NARFL deficiency and eventually diffuse PAVMs probably through VEGF pathway. In a word, we detected a functional mutation in NARFL, which might be the pathogenic gene in this pedigree. Impact Journals LLC 2016-11-07 /pmc/articles/PMC5356835/ /pubmed/27835862 http://dx.doi.org/10.18632/oncotarget.13156 Text en Copyright: © 2017 Liu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Liu, Hong-zhou Du, Chun-xian Luo, Jing Qiu, Xue-ping Li, Zu-hua Lou, Qi-yong Yin, Zhan Zheng, Fang A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations |
title | A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations |
title_full | A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations |
title_fullStr | A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations |
title_full_unstemmed | A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations |
title_short | A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations |
title_sort | novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356835/ https://www.ncbi.nlm.nih.gov/pubmed/27835862 http://dx.doi.org/10.18632/oncotarget.13156 |
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