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.

The morphological discrepancy of neuromuscular junctions between bilateral paraspinal muscles in patients with adolescent idiopathic scoliosis: A quantitative immunofluorescence assay

“… 8 Wang et al identified genetic variants of SLC6A9 in AIS, which led to the aberrant glycinergic neurotransmission, and slc6a9 mutant zebrafish exhibited discoordination of spinal neural activities and pronounced lateral spinal curvature, resembling human patients. 9 Shao et al found the deficiency of ESR1 in muscle progenitor cells of paraspinal muscles for AIS patients and imbalance of ESR1 signaling in bilateral paraspinal muscles induced scoliosis in mice. 10 These clues supported that the neuromuscular factors might be closely involved in the pathogenesis of AIS, but the exact mechanism still remained to be elucidated.…”