Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease.
Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease.
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作者：
过度兴奋是一种以过度惊吓反应为特征的人类神经系统疾病，通常由编码抑制性甘氨酸受体（GlyR）α1亚基（GLRA 1）的基因中的错义和无义突变引起。在其他突触后甘氨酸能蛋白（包括GlyR β亚基（GLRB）、桥蛋白（GPHN）和RhoGEF collybistin（ARHGEF 9））突变的孤立散发病例中证实了遗传异质性。然而，许多被诊断为过度兴奋的散发性患者并不携带这些基因的突变。在这里，我们揭示了突触前甘氨酸转运蛋白2（GlyT 2）基因（SLC 6A 5）的错义，无义和移码突变也会引起hyperekplexia。携带SLC 6A 5突变的患者表现为张力亢进、对触觉或听觉刺激的过度惊吓反应以及危及生命的新生儿呼吸暂停发作。GlyT 2突变导致亚细胞定位缺陷和/或甘氨酸摄取减少，选定的突变影响预测的甘氨酸和Na+结合位点。我们的研究结果表明，SLC 6A 5是一个主要基因的hyperkplexia和定义的第一个神经系统疾病与突变的Na+/Cl−依赖转运的经典快速神经递质。通过类比，我们认为，在其他人类疾病的缺陷，突触后受体已被确定，类似的症状可能会导致同源突触前神经递质转运蛋白的缺陷。
Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) α1 subunit (GLRA1). Genetic heterogeneity has been confirmed in isolated sporadic cases with mutations in other postsynaptic glycinergic proteins including the GlyR β subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many sporadic patients diagnosed with hyperekplexia do not carry mutations in these genes. Here we reveal that missense, nonsense and frameshift mutations in the presynaptic glycine transporter 2 (GlyT2) gene (SLC6A5) also cause hyperekplexia. Patients harbouring mutations in SLC6A5 presented with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnoea episodes. GlyT2 mutations result in defective subcellular localisation and/or decreased glycine uptake, with selected mutations affecting predicted glycine and Na+ binding sites. Our results demonstrate that SLC6A5 is a major gene for hyperekplexia and define the first neurological disorder linked to mutations in a Na+/Cl−-dependent transporter for a classical fast neurotransmitter. By analogy, we suggest that in other human disorders where defects in postsynaptic receptors have been identified, similar symptoms could result from defects in the cognate presynaptic neurotransmitter transporter.
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DOI：
10.1073/pnas.041329498
发表时间：
2001-02-13
影响因子：
11.1
作者：
Horiuchi, M;Nicke, A;Betz, H
通讯作者：
Betz, H
影响因子：
3.6
作者：
Hahn, MK;Mazei-Robison, MC;Blakely, RD
通讯作者：
Blakely, RD
影响因子：
1.9
作者：
Vergouwe, MN;Tijssen, MAJ;Frants, RR
通讯作者：
Frants, RR
影响因子：
5.3
作者：
Rees, MI;Lewis, TM;Owen, MJ
通讯作者：
Owen, MJ
影响因子：
30.8
作者：
SHIANG, R;RYAN, SG;WASMUTH, JJ
通讯作者：
WASMUTH, JJ