Impaired glycine neurotransmission causes adolescent idiopathic scoliosis
Xiaolu Wang, … , You-Qiang Song, Bo Gao
Xiaolu Wang, … , You-Qiang Song, Bo Gao
Published November 14, 2023
Citation Information: J Clin Invest. 2024;134(2):e168783. https://doi.org/10.1172/JCI168783.
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Research Article Bone biology Genetics

Impaired glycine neurotransmission causes adolescent idiopathic scoliosis

Abstract

Adolescent 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.

Authors

Xiaolu Wang, Ming Yue, Jason Pui Yin Cheung, Prudence Wing Hang Cheung, Yanhui Fan, Meicheng Wu, Xiaojun Wang, Sen Zhao, Anas M. Khanshour, Jonathan J. Rios, Zheyi Chen, Xiwei Wang, Wenwei Tu, Danny Chan, Qiuju Yuan, Dajiang Qin, Guixing Qiu, Zhihong Wu, Terry Jianguo Zhang, Shiro Ikegawa, Nan Wu, Carol A. Wise, Yong Hu, Keith Dip Kei Luk, You-Qiang Song, Bo Gao

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Figure 4

Body curvature in slc6a9 mutant zebrafish.

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Body curvature in slc6a9 mutant zebrafish. (A) Axial curvature of slc6a9...
(A) Axial curvature of slc6a9 mutant zebrafish at 7 dpf. The severity of the curvature is measured by θ angle. (B) Spinal curvature of slc6a9 mutant zebrafish at 21 dpf. (C) Curvature phenotype and micro-CT images of WT and slc6a9m/+ zebrafish at adolescent stage (35 dpf). Images are shown in either side or dorsal view. A, anterior; P, posterior; L, left; R, right. (D) Axial curvature of WT zebrafish larvae treated with vehicle or GLYT1 inhibitor ALX 5407 (1 μM). (E) Quantification of axial curvature in WT and slc6a9m/+ zebrafish treated with vehicle (Veh) or low-dose ALX5407 (ALX, 10 nM). Only 10% of slc6a9m/+ fish showed axial curvature (θ ≥10°), whereas 10 nM ALX5407 induced axial curvature in 4.65% of WT and 34.9% of slc6a9m/+ fish. (F) Quantification of axial curvature in slc6a9m/m zebrafish with and without injection of 200 pg SLC6A9 WT or mutant (Y206F or R662W) mRNAs. Scale bars: 1 mm (A and D); 2 mm (B and C). In all charts, boxes show the median and IQRs with all individual data points superimposed. The number of analyzed fish and the penetrance of curvature (θ ≥10°) are quantified and indicated for each genotype. Unpaired Student’s t test (D) or 1-way ANOVA test (A, E, and F). **P < 0.01; ****P < 0.0001.