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 6

Prevention of body curvature in slc6a9 mutant zebrafish by pharmacological intervention.

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Prevention of body curvature in slc6a9 mutant zebrafish by pharmacologic...
(A) Representative dorsal-view images of axial phenotypes of WT and slc6a9m/m larvae treated with vehicle or strychnine (GlyR antagonist, 0.5 μM). (B) Representative dorsal-view images of axial phenotypes of WT and slc6a9m/m larvae treated with vehicle or sodium benzoate (glycine neutralizer, 0.5 ppm). Scale bars: 1 mm. In A and B, the number of analyzed fish and the penetrance of curvature are quantified and indicated for each genotype. Boxes show the median and IQRs with all individual data points superimposed. One-way ANOVA test. **P < 0.01; ****P < 0.0001. (C) Proposed glycinopathy spectrum. Abnormally high levels of glycine are associated with glycine encephalopathy, a severe neurological disease, whereas moderately elevated levels of glycine are a causal risk factor for AIS. (D) Cellular component of GO functional enrichment analysis of AIS-associated genes. GeneRatio is the ratio of genes mapped to a pathway to the total gene set. The size of the dots represents the number of genes mapped to the pathway. (E) Proposed disease mechanism of spinal curvature. In zebrafish, disruption of glyt1 causes a discoordination of left-right neural activities in the spinal cord due to aberrant glycinergic neurotransmission; deletion of dmrt3a partially impairs the development of commissural interneurons and compromises the locomotor left-right alternation; both lead to an AIS-like phenotype via the disturbance of CPGs in the spinal cord. In humans, functional impairment of GLYT1 leads to elevated glycine levels, aberrant paraspinal muscle activities, and AIS. Our findings suggest that dysfunction of the CPGs induced by either excessive glycine or developmental defects is one of the major causal factors underlying the etiology of AIS. I.N., interneurons; M.N., motoneurons.