Cargando…

Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea

Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and w...

Descripción completa

Detalles Bibliográficos
Autores principales: Deng, Zhili, Chen, Mengting, Zhao, Zhixiang, Xiao, Wenqin, Liu, Tangxiele, Peng, Qinqin, Wu, Zheng, Xu, San, Shi, Wei, Jian, Dan, Wang, Ben, Liu, Fangfen, Tang, Yan, Huang, Yingxue, Zhang, Yiya, Wang, Qian, Sun, Lunquan, Xie, Hongfu, Zhang, Guohong, Li, Ji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319783/
https://www.ncbi.nlm.nih.gov/pubmed/37402769
http://dx.doi.org/10.1038/s41467-023-39761-2
_version_ 1785068311289004032
author Deng, Zhili
Chen, Mengting
Zhao, Zhixiang
Xiao, Wenqin
Liu, Tangxiele
Peng, Qinqin
Wu, Zheng
Xu, San
Shi, Wei
Jian, Dan
Wang, Ben
Liu, Fangfen
Tang, Yan
Huang, Yingxue
Zhang, Yiya
Wang, Qian
Sun, Lunquan
Xie, Hongfu
Zhang, Guohong
Li, Ji
author_facet Deng, Zhili
Chen, Mengting
Zhao, Zhixiang
Xiao, Wenqin
Liu, Tangxiele
Peng, Qinqin
Wu, Zheng
Xu, San
Shi, Wei
Jian, Dan
Wang, Ben
Liu, Fangfen
Tang, Yan
Huang, Yingxue
Zhang, Yiya
Wang, Qian
Sun, Lunquan
Xie, Hongfu
Zhang, Guohong
Li, Ji
author_sort Deng, Zhili
collection PubMed
description Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and whole exome sequencing (WES) in 49 additional validation families. We identify single rare deleterious variants of LRRC4, SH3PXD2A and SLC26A8 in large families, respectively. The relevance of SH3PXD2A, SLC26A8 and LRR family genes in rosacea predisposition is underscored by presence of additional variants in independent families. Gene ontology analysis suggests that these genes encode proteins taking part in neural synaptic processes and cell adhesion. In vitro functional analysis shows that mutations in LRRC4, SH3PXD2A and SLC26A8 induce the production of vasoactive neuropeptides in human neural cells. In a mouse model recapitulating a recurrent Lrrc4 mutation from human patients, we find rosacea-like skin inflammation, underpinned by excessive vasoactive intestinal peptide (VIP) release by peripheral neurons. These findings strongly support familial inheritance and neurogenic inflammation in rosacea development and provide mechanistic insight into the etiopathogenesis of the condition.
format Online
Article
Text
id pubmed-10319783
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-103197832023-07-06 Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea Deng, Zhili Chen, Mengting Zhao, Zhixiang Xiao, Wenqin Liu, Tangxiele Peng, Qinqin Wu, Zheng Xu, San Shi, Wei Jian, Dan Wang, Ben Liu, Fangfen Tang, Yan Huang, Yingxue Zhang, Yiya Wang, Qian Sun, Lunquan Xie, Hongfu Zhang, Guohong Li, Ji Nat Commun Article Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and whole exome sequencing (WES) in 49 additional validation families. We identify single rare deleterious variants of LRRC4, SH3PXD2A and SLC26A8 in large families, respectively. The relevance of SH3PXD2A, SLC26A8 and LRR family genes in rosacea predisposition is underscored by presence of additional variants in independent families. Gene ontology analysis suggests that these genes encode proteins taking part in neural synaptic processes and cell adhesion. In vitro functional analysis shows that mutations in LRRC4, SH3PXD2A and SLC26A8 induce the production of vasoactive neuropeptides in human neural cells. In a mouse model recapitulating a recurrent Lrrc4 mutation from human patients, we find rosacea-like skin inflammation, underpinned by excessive vasoactive intestinal peptide (VIP) release by peripheral neurons. These findings strongly support familial inheritance and neurogenic inflammation in rosacea development and provide mechanistic insight into the etiopathogenesis of the condition. Nature Publishing Group UK 2023-07-05 /pmc/articles/PMC10319783/ /pubmed/37402769 http://dx.doi.org/10.1038/s41467-023-39761-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Deng, Zhili
Chen, Mengting
Zhao, Zhixiang
Xiao, Wenqin
Liu, Tangxiele
Peng, Qinqin
Wu, Zheng
Xu, San
Shi, Wei
Jian, Dan
Wang, Ben
Liu, Fangfen
Tang, Yan
Huang, Yingxue
Zhang, Yiya
Wang, Qian
Sun, Lunquan
Xie, Hongfu
Zhang, Guohong
Li, Ji
Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
title Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
title_full Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
title_fullStr Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
title_full_unstemmed Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
title_short Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
title_sort whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319783/
https://www.ncbi.nlm.nih.gov/pubmed/37402769
http://dx.doi.org/10.1038/s41467-023-39761-2
work_keys_str_mv AT dengzhili wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT chenmengting wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT zhaozhixiang wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT xiaowenqin wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT liutangxiele wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT pengqinqin wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT wuzheng wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT xusan wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT shiwei wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT jiandan wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT wangben wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT liufangfen wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT tangyan wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT huangyingxue wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT zhangyiya wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT wangqian wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT sunlunquan wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT xiehongfu wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT zhangguohong wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea
AT liji wholegenomesequencingidentifiesgeneticvariantsassociatedwithneurogenicinflammationinrosacea