Impaired glycine neurotransmission causes adolescent idiopathic scoliosis
Publication in refereed journal
Full Text
View Full-text in CUHK Digital Object Identifier (DOI)  |
Altmetrics Information
.
Other information
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.
All Author(s) ListWang X., Yue M., Cheung J.P.Y., Cheung P.W.H., Fan Y., Wu M., Wang X., Zhao S., Khanshour A.M., Rios J.J., Chen Z., Wang X., Tu W., Chan D., Yuan Q., Qin D., Qiu G., Wu Z., Zhang T.J., Ikegawa S., Wu N., Wise C.A., Hu Y., Luk K.D.K., Song Y.Q., Gao B.
Journal nameJournal of Clinical Investigation
Year2024
Month1
Day1
Volume Number134
Issue Number2
PublisherAmerican Society for Clinical Investigation
Article numbere168783
ISSN0021-9738
eISSN1558-8238
LanguagesEnglish-United Kingdom
KeywordsBone Biology, Bone disease, Genetic diseases, Genetics, Orthopedics
