Impaired glycine neurotransmission causes adolescent idiopathic scoliosis

Abstract

<p>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. As such, treatment of AIS is limited to bracing and/or invasive surgery post onset. Pre-onset diagnosis or preventive treatment remains unavailable. Here we performed a genetic analysis of a large multi-center AIS cohort and identified disease-causing and predisposing variants of SLC6A9 in multi-generation families, trios, and sporadic patients. Variants of SLC6A9, which encodes glycine transporter 1 (GLYT1), reduced glycine uptake activity in cells, leading to an increased extracellular glycine level 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 was 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.</p>