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.

中文翻译：

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甘氨酸神经传递受损导致青少年特发性脊柱侧凸

青少年特发性脊柱侧凸（AIS）是最常见的脊柱畸形形式，影响着全世界数百万青少年，但缺乏明确的发病机制理论。因此，AIS 的治疗仅限于发病后进行支具和/或侵入性手术。尚无法进行发病前诊断或预防性治疗。在这里，我们对大型多中心 AIS 队列进行了遗传分析，并在多代家庭、三人组和散发患者中鉴定了SLC6A9的致病和易感变异。编码甘氨酸转运蛋白 1 (GLYT1) 的SLC6A9变体降低了细胞中的甘氨酸摄取活性，导致细胞外甘氨酸水平增加和异常的甘氨酸神经传递。Slc6a9突变斑马鱼表现出脊髓神经活动不协调和明显的脊柱侧向弯曲，这种表型类似于人类患者。外显率和弯曲的严重程度对功能性glyt1的剂量敏感。给予甘氨酸受体拮抗剂或临床使用的甘氨酸中和剂（苯甲酸钠）可部分挽救该表型。我们的研究结果表明“特发性”脊柱侧凸的神经源性，涉及突触神经传递和中枢模式发生器（CPG）的功能障碍，这可能是 AIS 的常见原因。我们的工作进一步提出了青春期前 AIS 早期诊断和干预的途径。