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Article: Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis

TitleRare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis
Authors
Keywordsadolescent idiopathic scoliosis
CRISPR/Cas9
MAPK7
whole-exome sequencing
zebrafish
Issue Date2017
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/38515
Citation
Human Mutation, 2017, v. 38 n. 11, p. 1500-1510 How to Cite?
AbstractAdolescent 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.
Persistent Identifierhttp://hdl.handle.net/10722/258484
ISSN
2017 Impact Factor: 5.359
2015 SCImago Journal Rankings: 3.670
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGao, WJ-
dc.contributor.authorChen, C-
dc.contributor.authorZhou, TF-
dc.contributor.authorYang, SL-
dc.contributor.authorGao, B-
dc.contributor.authorZhou, H-
dc.contributor.authorLian, CJ-
dc.contributor.authorWu, ZZ-
dc.contributor.authorQiu, XJ-
dc.contributor.authorYang, XM-
dc.contributor.authorAlattar, E-
dc.contributor.authorLiu, WT-
dc.contributor.authorSu, DY-
dc.contributor.authorChen, YL-
dc.contributor.authorCheung, KMC-
dc.contributor.authorSong, Y-
dc.contributor.authorLuk, KDK-
dc.contributor.authorChan, D-
dc.contributor.authorSham, PC-
dc.contributor.authorXing, C-
dc.contributor.authorKhor, CC-
dc.contributor.authorLiu, G-
dc.contributor.authorYang, JL-
dc.contributor.authorDeng, YB-
dc.contributor.authorHao, DJ-
dc.contributor.authorHuang, DS-
dc.contributor.authorLi, QZ-
dc.contributor.authorXu, CX-
dc.contributor.authorSu, PQ-
dc.date.accessioned2018-08-22T01:39:11Z-
dc.date.available2018-08-22T01:39:11Z-
dc.date.issued2017-
dc.identifier.citationHuman Mutation, 2017, v. 38 n. 11, p. 1500-1510-
dc.identifier.issn1059-7794-
dc.identifier.urihttp://hdl.handle.net/10722/258484-
dc.description.abstractAdolescent 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.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/38515-
dc.relation.ispartofHuman Mutation-
dc.rightsHuman Mutation. Copyright © John Wiley & Sons, Inc.-
dc.rightsPreprint: This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Postprint: This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Special Statement for Preprint only Before publication: 'This is a preprint of an article accepted for publication in [The Journal of Pathology] Copyright © ([year]) ([Pathological Society of Great Britain and Ireland])'. After publication: the preprint notice should be amended to follows: 'This is a preprint of an article published in [include the complete citation information for the final version of the Contribution as published in the print edition of the Journal]' For Cochrane Library/ Cochrane Database of Systematic Reviews, add statement & acknowledgement : ‘This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 20XX, Issue X. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.’ Please include reference to the Review and hyperlink to the original version using the following format e.g. Authors. Title of Review. Cochrane Database of Systematic Reviews 20XX, Issue #. Art. No.: CD00XXXX. DOI: 10.1002/14651858.CD00XXXX (insert persistent link to the article by using the URL: http://dx.doi.org/10.1002/14651858.CD00XXXX) (This statement should refer to the most recent issue of the Cochrane Database of Systematic Reviews in which the Review published.)-
dc.subjectadolescent idiopathic scoliosis-
dc.subjectCRISPR/Cas9-
dc.subjectMAPK7-
dc.subjectwhole-exome sequencing-
dc.subjectzebrafish-
dc.titleRare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis-
dc.typeArticle-
dc.identifier.emailCheung, KMC: hcm21000@hku.hk-
dc.identifier.emailSong, Y: songy@hku.hk-
dc.identifier.emailLuk, KDK: hrmoldk@HKUCC-COM.hku.hk-
dc.identifier.emailChan, D: chand@hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.authorityCheung, KMC=rp00387-
dc.identifier.authoritySong, Y=rp00488-
dc.identifier.authorityLuk, KDK=rp00333-
dc.identifier.authorityChan, D=rp00540-
dc.identifier.authoritySham, PC=rp00459-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/humu.23296-
dc.identifier.pmid28714182-
dc.identifier.scopuseid_2-s2.0-85026299151-
dc.identifier.hkuros286442-
dc.identifier.volume38-
dc.identifier.issue11-
dc.identifier.spage1500-
dc.identifier.epage1510-
dc.identifier.isiWOS:000412835700008-
dc.publisher.placeUnited States-

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