Impaired glycine neurotransmission causes adolescent idiopathic scoliosis.
Impaired glycine neurotransmission causes adolescent idiopathic scoliosis.
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DOI：
10.1172/jci168783
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发表时间：
2024-01-16
影响因子：
15.9
通讯作者：
Guo, Bo
中科院分区：
文献类型：
--
作者：
Wang, Xiaolu;Yue, Ming;Cheung, Jason Pui Yin;Cheung, Prudence Wing Hang;Fan, Yanhui;Wu, Meicheng;Wang, Xiaojun;Zhao, Sen;Khanshour, Anas M.;Rios, Jonathan J.;Chen, Zheyi;Wang, Xiwei;Tu, Wenwei;Chan, Danny;Yuan, Qiuju;Qin, Dajiang;Qiu, Guixing;Wu, Zhihong;Zhang, Terry Jianguo;Ikegawa, Shiro;Wu, Nan;Wise, Carol A.;Hu, Yong;Luk, Keith Dip Kei;Song, You-Qiang;Guo, Bo
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的支具和/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，我们对一个大型多中心 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”脊柱侧弯的神经源性，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。影响突触神经传递和中枢模式生成器的遗传变异是青少年特发性脊柱侧凸的重要危险因素。
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. Genetic variants affecting synaptic neurotransmission and central pattern generators are strong causal risk factors of adolescent idiopathic scoliosis.
影响因子：
5.3
作者：
Alfadhel, Majid;Nashabat, Marwan;Al Qahtani, Hanan;Alfares, Ahmed;Al Mutairi, Fuad;Al Shaalan, Hesham;Douglas, Ganka V.;Wierenga, Klaas;Juusola, Jane;Alrifai, Muhammad Talal;Arold, Stefan T.;Alkuraya, Fowzan;Abu Ali, Qais
通讯作者：
Abu Ali, Qais
影响因子：
3.9
作者：
Terhune EA;Cuevas MT;Monley AM;Wethey CI;Chen X;Cattell MV;Bayrak MN;Bland MR;Sutphin B;Trahan GD;Taylor MRG;Niswander LA;Jones KL;Baschal EE;Antunes L;Dobbs M;Gurnett C;Appel B;Gray R;Hadley Miller N
通讯作者：
Hadley Miller N