@article{02072102da254c98844e68291b71b919,
title = "Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis",
abstract = "Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder characterized by three-dimensional spinal curvatures, affecting 2%–3% of school age children, yet the causes underlying AIS are not well understood. Here, we first conducted a whole-exome sequencing and linkage analysis on a three-generation Chinese family with autosomal-dominant (AD) AIS, and then performed targeted sequencing in a discovery cohort comprising 20 AD AIS families and 86 simplex patients, and finally identified three disease-associated missense variants (c.886G> A, c.1943C> T, and c.1760C> T) in the MAPK7 gene (encoding mitogen-activated protein kinase 7). Genotyping of the three rare variants in a Chinese replication cohort comprising 1,038 simplex patients and 1,841 controls showed that their combined allele frequency was significantly over-represented in patients as compared with controls (2.0% [41/2,076] vs. 0.7% [27/3,682]; odds ratio = 2.7; P = 2.8 × 10−5). In vitro, we demonstrated that the three MAPK7 mutants disrupted nuclear translocation in cellular models, which is necessary for the normal function of MAPK7. In vivo, we also conducted CRISPR/Cas9-mediated deletion of mapk7 in zebrafish recapitulating the characteristic phenotype of idiopathic scoliosis. Taken together, our findings suggest that rare coding variants in MAPK7 predispose to AIS, providing clues to understanding the mechanisms of AIS.",
keywords = "CRISPR/Cas9, MAPK7, adolescent idiopathic scoliosis, whole-exome sequencing, zebrafish",
author = "Wenjie Gao and Chong Chen and Taifeng Zhou and Shulan Yang and Bo Gao and Hang Zhou and Chengjie Lian and Zizhao Wu and Xianjian Qiu and Xiaoming Yang and Esam Alattar and Wentao Liu and Deying Su and Silong Sun and Yulan Chen and Cheung, {Kenneth M.C.} and Youqiang Song and Luk, {Keith K.D.} and Danny Chan and Sham, {Pak Chung} and Chao Xing and Khor, {Chiea Chuen} and Gabriel Liu and Junlin Yang and Yubin Deng and Dingjun Hao and Dongsheng Huang and Li, {Quan Zhen} and Caixia Xu and Peiqiang Su",
note = "Funding Information: We thank the patients and controls who participated in this project. We are grateful to Carol A. Wise (Seay Center for Musculoskeletal Research, Texas Scottish RiteHospital for Children, Dallas) for technical training; Sharma Swarkar (Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas; and School of Biology and Chemistry, Shri Mata Vaishno Devi University, Katra, India) for help in statistical analyses of the WES data; and Ya-Di Liao (Sun Yat-sen University Cancer Centre, Guangzhou, China) for help in graphic editing. The authors have no conflict of interest to declare. Funding Information: Contract grant sponsors: National Natural Science Foundation of China (Nos. 81371908, 81472039, 81572091, 81601898); the China Postdoctoral Science Foundation (No. 2017M613177); the Program for New Century Excellent Talents in University (NCET-12-0564); Fundamental Research Funds for the Central Universities; Young Teachers Fund of the Sun Yat-Sen University (13YKPY23). Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",
year = "2017",
month = nov,
doi = "10.1002/humu.23296",
language = "English (US)",
volume = "38",
pages = "1500--1510",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "11",
}