Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
Abstract 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 famil...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39761-2 |
| _version_ | 1797784465132486656 |
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| author | Zhili Deng Mengting Chen Zhixiang Zhao Wenqin Xiao Tangxiele Liu Qinqin Peng Zheng Wu San Xu Wei Shi Dan Jian Ben Wang Fangfen Liu Yan Tang Yingxue Huang Yiya Zhang Qian Wang Lunquan Sun Hongfu Xie Guohong Zhang Ji Li |
| author_facet | Zhili Deng Mengting Chen Zhixiang Zhao Wenqin Xiao Tangxiele Liu Qinqin Peng Zheng Wu San Xu Wei Shi Dan Jian Ben Wang Fangfen Liu Yan Tang Yingxue Huang Yiya Zhang Qian Wang Lunquan Sun Hongfu Xie Guohong Zhang Ji Li |
| author_sort | Zhili Deng |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-13T00:40:16Z |
| format | Article |
| id | doaj.art-02806b4507eb41b3a56a9c267149c09d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T00:40:16Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-02806b4507eb41b3a56a9c267149c09d2023-07-09T11:19:11ZengNature PortfolioNature Communications2041-17232023-07-0114111510.1038/s41467-023-39761-2Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosaceaZhili Deng0Mengting Chen1Zhixiang Zhao2Wenqin Xiao3Tangxiele Liu4Qinqin Peng5Zheng Wu6San Xu7Wei Shi8Dan Jian9Ben Wang10Fangfen Liu11Yan Tang12Yingxue Huang13Yiya Zhang14Qian Wang15Lunquan Sun16Hongfu Xie17Guohong Zhang18Ji Li19Department of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityHunan Binsis Biotechnology Co., LtdNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Dermatology, Xiangya Hospital, Central South UniversityDepartment of Pathology, Shantou University Medical CollegeDepartment of Dermatology, Xiangya Hospital, Central South UniversityAbstract 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.https://doi.org/10.1038/s41467-023-39761-2 |
| spellingShingle | Zhili Deng Mengting Chen Zhixiang Zhao Wenqin Xiao Tangxiele Liu Qinqin Peng Zheng Wu San Xu Wei Shi Dan Jian Ben Wang Fangfen Liu Yan Tang Yingxue Huang Yiya Zhang Qian Wang Lunquan Sun Hongfu Xie Guohong Zhang Ji Li Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea Nature Communications |
| 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 |
| url | https://doi.org/10.1038/s41467-023-39761-2 |
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