Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes

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

doi:10.3389/fcell.2020.582255

Frontiers in Cell and Developmental Biology (Nov 2020)

Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes

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

Affiliations

Yunjia Wang: Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
Yunjia Wang: National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Yunjia Wang: Department of Pediatrics, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School, Austin, TX, United States
Zhenhao Liu: Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, China
Zhenhao Liu: Key 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, China
Guanteng Yang: Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
Guanteng Yang: National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Qile Gao: Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
Qile Gao: National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Lige Xiao: Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
Lige Xiao: National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Jiong Li: Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
Jiong Li: National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Chaofeng Guo: Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
Chaofeng Guo: National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Benjamin R. Troutwine: Department of Pediatrics, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School, Austin, TX, United States
Ryan S. Gray: Department of Pediatrics, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School, Austin, TX, United States
Lu Xie: Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, China
Hongqi Zhang: Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
Hongqi Zhang: National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China

DOI: https://doi.org/10.3389/fcell.2020.582255
Journal volume & issue: Vol. 8

Abstract

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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.

Published in Frontiers in Cell and Developmental Biology

ISSN: 2296-634X (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Science: Biology (General)
Website: https://www.frontiersin.org/journals/cell-and-developmental-biology

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