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Article: Impaired glycine neurotransmission causes adolescent idiopathic scoliosis

TitleImpaired glycine neurotransmission causes adolescent idiopathic scoliosis
Authors
Issue Date2024
Citation
Journal of Clinical Investigation, 2024, v. 134, n. 2, article no. e168783 How to Cite?
AbstractAdolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting millions of adolescents worldwide, but it lacks a defined theory of etiopathogenesis. Because of this, treatment of AIS is limited to bracing and/or invasive surgery after onset. Preonset diagnosis or preventive treatment remains unavailable. Here, we performed a genetic analysis of a large multicenter AIS cohort and identified disease-causing and predisposing variants of SLC6A9 in multigeneration families, trios, and sporadic patients. Variants of SLC6A9, which encodes glycine transporter 1 (GLYT1), reduced glycine-uptake activity in cells, leading to increased extracellular glycine levels and aberrant glycinergic neurotransmission. Slc6a9 mutant zebrafish exhibited discoordination of spinal neural activities and pronounced lateral spinal curvature, a phenotype resembling human patients. The penetrance and severity of curvature were sensitive to the dosage of functional glyt1. Administration of a glycine receptor antagonist or a clinically used glycine neutralizer (sodium benzoate) partially rescued the phenotype. Our results indicate a neuropathic origin for “idiopathic” scoliosis, involving the dysfunction of synaptic neurotransmission and central pattern generators (CPGs), potentially a common cause of AIS. Our work further suggests avenues for early diagnosis and intervention of AIS in preadolescents.
Persistent Identifierhttp://hdl.handle.net/10722/343450
ISSN
2023 Impact Factor: 13.3
2023 SCImago Journal Rankings: 4.833

 

DC FieldValueLanguage
dc.contributor.authorWang, Xiaolu-
dc.contributor.authorYue, Ming-
dc.contributor.authorCheung, Jason Pui Yin-
dc.contributor.authorCheung, Prudence Wing Hang-
dc.contributor.authorFan, Yanhui-
dc.contributor.authorWu, Meicheng-
dc.contributor.authorWang, Xiaojun-
dc.contributor.authorZhao, Sen-
dc.contributor.authorKhanshour, Anas M.-
dc.contributor.authorRios, Jonathan J.-
dc.contributor.authorChen, Zheyi-
dc.contributor.authorWang, Xiwei-
dc.contributor.authorTu, Wenwei-
dc.contributor.authorChan, Danny-
dc.contributor.authorYuan, Qiuju-
dc.contributor.authorQin, Dajiang-
dc.contributor.authorQiu, Guixing-
dc.contributor.authorWu, Zhihong-
dc.contributor.authorZhang, Terry Jianguo-
dc.contributor.authorIkegawa, Shiro-
dc.contributor.authorWu, Nan-
dc.contributor.authorWise, Carol A.-
dc.contributor.authorHu, Yong-
dc.contributor.authorLuk, Keith Dip Kei-
dc.contributor.authorSong, You Qiang-
dc.contributor.authorGao, Bo-
dc.date.accessioned2024-05-10T09:08:14Z-
dc.date.available2024-05-10T09:08:14Z-
dc.date.issued2024-
dc.identifier.citationJournal of Clinical Investigation, 2024, v. 134, n. 2, article no. e168783-
dc.identifier.issn0021-9738-
dc.identifier.urihttp://hdl.handle.net/10722/343450-
dc.description.abstractAdolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting millions of adolescents worldwide, but it lacks a defined theory of etiopathogenesis. Because of this, treatment of AIS is limited to bracing and/or invasive surgery after onset. Preonset diagnosis or preventive treatment remains unavailable. Here, we performed a genetic analysis of a large multicenter AIS cohort and identified disease-causing and predisposing variants of SLC6A9 in multigeneration families, trios, and sporadic patients. Variants of SLC6A9, which encodes glycine transporter 1 (GLYT1), reduced glycine-uptake activity in cells, leading to increased extracellular glycine levels and aberrant glycinergic neurotransmission. Slc6a9 mutant zebrafish exhibited discoordination of spinal neural activities and pronounced lateral spinal curvature, a phenotype resembling human patients. The penetrance and severity of curvature were sensitive to the dosage of functional glyt1. Administration of a glycine receptor antagonist or a clinically used glycine neutralizer (sodium benzoate) partially rescued the phenotype. Our results indicate a neuropathic origin for “idiopathic” scoliosis, involving the dysfunction of synaptic neurotransmission and central pattern generators (CPGs), potentially a common cause of AIS. Our work further suggests avenues for early diagnosis and intervention of AIS in preadolescents.-
dc.languageeng-
dc.relation.ispartofJournal of Clinical Investigation-
dc.titleImpaired glycine neurotransmission causes adolescent idiopathic scoliosis-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1172/JCI168783-
dc.identifier.pmid37962965-
dc.identifier.scopuseid_2-s2.0-85182595751-
dc.identifier.volume134-
dc.identifier.issue2-
dc.identifier.spagearticle no. e168783-
dc.identifier.epagearticle no. e168783-
dc.identifier.eissn1558-8238-

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