PUBLICATION

Impaired glycine neurotransmission causes adolescent idiopathic scoliosis

Authors
Wang, 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, J., Ikegawa, S., Wu, N., Wise, C.A., Hu, Y., Luk, K.D.K., Song, Y.Q., Gao, B.
ID
ZDB-PUB-231115-4
Date
2023
Source
The Journal of Clinical Investigation   134(2): (Journal)
Registered Authors
Gao, Bo
Keywords
Bone Biology, Bone disease, Genetic diseases, Genetics, Orthopedics
MeSH Terms
  • Scoliosis*/diagnosis
  • Scoliosis*/genetics
  • Scoliosis*/surgery
  • Adolescent
  • Synaptic Transmission
  • Humans
  • Glycine/genetics
  • Zebrafish
  • Animals
(all 9)
PubMed
37962965 Full text @ Journal of Clin. Invest.
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. 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.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
GCaMPjf5Tgstandard conditionsPrim-5IFL
GCaMPslc6a9chk1/chk1; jf5Tgstandard conditionsPrim-5IFL
1 - 2 of 2
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Phenotype
Fish Conditions Stage Phenotype Figure
TUchemical treatment by environment: ALX 5407 hydrochlorideDays 7-13
TUchemical treatment by environment: sodium benzoateDays 7-13
TUchemical treatment by environment: strychnineDays 7-13
dmrt3achk2/+ (TU)standard conditionsDays 21-29
dmrt3achk2/chk2 (TU)standard conditionsDays 21-29
dmrt3achk2/chk2 (TU)standard conditionsAdult
dmrt3achk2/chk2 (TU)standard conditionsAdult
slc6a9chk1/+ (TU)standard conditionsDays 7-13
slc6a9chk1/+ (TU)standard conditionsDays 21-29
slc6a9chk1/+ (TU)standard conditionsDays 21-29
1 - 10 of 20
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
chk1
    		Small Deletion
    chk2
      		Small Deletion
      jf5TgTransgenic Insertion
        ml2TgTransgenic Insertion
          ta229g
            		Unknown
            1 - 5 of 5
            Show
            Human Disease / Model
            Human Disease Fish Conditions Evidence
            idiopathic scoliosisslc6a9chk1/chk1 (TU)standard conditionsTAS
            idiopathic scoliosisslc6a9chk1/+ (TU)standard conditionsTAS
            1 - 2 of 2
            Show
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            dmrt3aCRISPR2-dmrt3aCRISPR
            slc6a9CRISPR1-slc6a9CRISPR
            1 - 2 of 2
            Show
            Fish
            Fish
            dmrt3achk2/chk2 (TU)
            dmrt3achk2/+ (TU)
            jf5Tg
            slc6a9chk1/chk1; jf5Tg
            slc6a9chk1/chk1 (TU)
            slc6a9chk1/+ (TU)
            TU
            1 - 7 of 7
            Show
            Antibodies
            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            GCaMPEFGGCaMP
            GFPEFGGFP
            1 - 2 of 2
            Show
            Mapping
            No data available
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            Citation
            Wang, 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, J., Ikegawa, S., Wu, N., Wise, C.A., Hu, Y., Luk, K.D.K., Song, Y.Q., Gao, B. (2023) Impaired glycine neurotransmission causes adolescent idiopathic scoliosis. The Journal of Clinical Investigation. 134(2):.