Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes
Adolescent idiopathic scoliosis (AIS) is the most common pediatric spine disorder affecting ∼3% of children worldwide. Human genetic studies suggest a complex polygenic disease model for AIS with large genetic and phenotypic heterogeneity. However, the overall genetic etiology of AIS remains poorly...
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2020.582255/full |
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| author | Yunjia Wang Yunjia Wang Yunjia Wang Zhenhao Liu Zhenhao Liu Guanteng Yang Guanteng Yang Qile Gao Qile Gao Lige Xiao Lige Xiao Jiong Li Jiong Li Chaofeng Guo Chaofeng Guo Benjamin R. Troutwine Ryan S. Gray Lu Xie Hongqi Zhang Hongqi Zhang |
| author_facet | Yunjia Wang Yunjia Wang Yunjia Wang Zhenhao Liu Zhenhao Liu Guanteng Yang Guanteng Yang Qile Gao Qile Gao Lige Xiao Lige Xiao Jiong Li Jiong Li Chaofeng Guo Chaofeng Guo Benjamin R. Troutwine Ryan S. Gray Lu Xie Hongqi Zhang Hongqi Zhang |
| author_sort | Yunjia Wang |
| collection | DOAJ |
| description | Adolescent idiopathic scoliosis (AIS) is the most common pediatric spine disorder affecting ∼3% of children worldwide. Human genetic studies suggest a complex polygenic disease model for AIS with large genetic and phenotypic heterogeneity. However, the overall genetic etiology of AIS remains poorly understood. To identify additional AIS susceptibility loci, we performed whole-exome sequencing (WES) on a cohort of 195 Southern Chinese AIS patients. Bioinformatics analysis identified 237 novel rare variants associated with AIS, located in 232 new susceptibility loci. Enrichment analysis of these variants revealed 10 gene families associated with our AIS cohort. We screened these gene families by comparing our candidate gene list with IS candidate genes in the Human Phenotype Ontology (HPO) database and previous reported studies. Two candidate gene families, axonemal dynein and axonemal dynein assembly factors, were retained for their associations with ciliary architecture and function. The damaging effects of candidate variants in dynein genes dnali1, dnah1, dnaaf, and zmynd10, as well as in one fibrillin-related gene tns1, were functionally analyzed in zebrafish using targeted CRISPR/Cas9 screening. Knockout of two candidate genes, dnaaf1 or zmynd10, recapitulated scoliosis in viable adult zebrafish. Altogether, our results suggest that the disruption of one or more dynein-associated factors may correlate with AIS susceptibility in the Southern Chinese population. |
| first_indexed | 2024-12-21T00:53:35Z |
| format | Article |
| id | doaj.art-70830f076ec64305bb420f9c14282006 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-21T00:53:35Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-70830f076ec64305bb420f9c142820062022-12-21T19:21:21ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-11-01810.3389/fcell.2020.582255582255Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate GenesYunjia Wang0Yunjia Wang1Yunjia Wang2Zhenhao Liu3Zhenhao Liu4Guanteng Yang5Guanteng Yang6Qile Gao7Qile Gao8Lige Xiao9Lige Xiao10Jiong Li11Jiong Li12Chaofeng Guo13Chaofeng Guo14Benjamin R. Troutwine15Ryan S. Gray16Lu Xie17Hongqi Zhang18Hongqi Zhang19Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Pediatrics, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School, Austin, TX, United StatesShanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, ChinaKey Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, National Health and Family Planning Commission, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Pediatrics, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School, Austin, TX, United StatesDepartment of Pediatrics, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School, Austin, TX, United StatesShanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, ChinaDepartment of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, ChinaAdolescent idiopathic scoliosis (AIS) is the most common pediatric spine disorder affecting ∼3% of children worldwide. Human genetic studies suggest a complex polygenic disease model for AIS with large genetic and phenotypic heterogeneity. However, the overall genetic etiology of AIS remains poorly understood. To identify additional AIS susceptibility loci, we performed whole-exome sequencing (WES) on a cohort of 195 Southern Chinese AIS patients. Bioinformatics analysis identified 237 novel rare variants associated with AIS, located in 232 new susceptibility loci. Enrichment analysis of these variants revealed 10 gene families associated with our AIS cohort. We screened these gene families by comparing our candidate gene list with IS candidate genes in the Human Phenotype Ontology (HPO) database and previous reported studies. Two candidate gene families, axonemal dynein and axonemal dynein assembly factors, were retained for their associations with ciliary architecture and function. The damaging effects of candidate variants in dynein genes dnali1, dnah1, dnaaf, and zmynd10, as well as in one fibrillin-related gene tns1, were functionally analyzed in zebrafish using targeted CRISPR/Cas9 screening. Knockout of two candidate genes, dnaaf1 or zmynd10, recapitulated scoliosis in viable adult zebrafish. Altogether, our results suggest that the disruption of one or more dynein-associated factors may correlate with AIS susceptibility in the Southern Chinese population.https://www.frontiersin.org/articles/10.3389/fcell.2020.582255/fulladolescent idiopathic scoliosiswhole exome sequencingsouthern Chinese populationgenetic variationsbioinformatics analysisgene knockout |
| spellingShingle | Yunjia Wang Yunjia Wang Yunjia Wang Zhenhao Liu Zhenhao Liu Guanteng Yang Guanteng Yang Qile Gao Qile Gao Lige Xiao Lige Xiao Jiong Li Jiong Li Chaofeng Guo Chaofeng Guo Benjamin R. Troutwine Ryan S. Gray Lu Xie Hongqi Zhang Hongqi Zhang Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes Frontiers in Cell and Developmental Biology adolescent idiopathic scoliosis whole exome sequencing southern Chinese population genetic variations bioinformatics analysis gene knockout |
| title | Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes |
| title_full | Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes |
| title_fullStr | Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes |
| title_full_unstemmed | Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes |
| title_short | Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes |
| title_sort | coding variants coupled with rapid modeling in zebrafish implicate dynein genes dnaaf1 and zmynd10 as adolescent idiopathic scoliosis candidate genes |
| topic | adolescent idiopathic scoliosis whole exome sequencing southern Chinese population genetic variations bioinformatics analysis gene knockout |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2020.582255/full |
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