JBC：两项研究直指引发惊恐病基因突变的分子机制

近日，刊登在国际著名杂志《生物化学杂志》<em>Journal of Biological Chemistry</em>的两篇研究报告同时发现了某种基因的缺失会影响大脑对意外事件做出的反应。这种新型的遗传突变可以影响信号分子甘氨酸，甘氨酸主要负责在神经元细胞之间传递信息，其是在不同种细胞中存在的小分子氨基酸。

在惊恐症中，缺失的蛋白质可以抑制细胞接收抑制信号，结果会导致机体的有害效应。惊恐症是有编码甘氨酸信号分子的不同基因突变所引发的。但是很多情况下这种情况并不涉及一个或多个基因的突变。斯旺西大学的研究者就发现了惊恐症引发的主要原因是编码甘氨酸转运蛋白GlyT2基因的缺失。

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另一项刊登在《生物化学杂志》上的研究报告也发现了编码甘氨酸转运蛋白GlyT2基因的缺失可以引发惊恐症，这种突变可以阻碍细胞膜中适当的甘氨酸转运蛋白的合成，并且改变其自身的功能。

研究者Corcuera解释道，GlyT2的突变可以降低甘氨酸吸收，浙江降低甘氨酸释放量，并且影响抑制信号的传递，这或许可以解释在病人中所观察的症状，而其对于未来开发新的疗法也很重要。

编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/08/120807132217.htm" target="_blank">Genetic Analyses Reveal Novel Mutations as Causes of Startle Disease</a>
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<a title="" href="http://dx.doi.org/doi:10.1074/jbc.M112.372094" target="_blank">doi:10.1074/jbc.M112.372094</a>
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<br/><strong>Mutations in the GlyT2 Gene (SLC6A5) Are a Second Major Cause of Startle Disease </strong><br/>


Eloisa Carta1, Seo-Kyung Chung2, Victoria M. James1, Angela Robinson2, Jennifer L. Gill1, Nathalie Remy3, Jean-Francois Vanbellinghen4, Cheney J. G. Drew2, Sophie Cagdas5, Duncan Cameron6, Frances M. Cowan7, Mireria Del Toro8, Gail E. Graham9, Adnan Y. Manzur10, Amira Masri11, Serge Rivera12, Emmanuel Scalais13, Rita Shiang14, Kate Sinclair15, Catriona A. Stuart16, Marina A. J. Tijssen17, Grahame Wise18, Sameer M. Zuberi19, Kirsten Harvey1, Brian R. Pearce1, Maya Topf20, Rhys H. Thomas2, Stephane Supplisson21, Mark I. Rees2 and Robert J. Harvey1,*

Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice-site mutations and large deletions in the human glycine receptor (GlyR) α1 subunit gene (GLRA1) are currently the major cause of this disorder. However, mutations are also found in the genes encoding GlyR β subunit (GLRB) and the presynaptic Na+/Cl--dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice-site mutations and missense mutations affecting residues implicated in Cl- binding, conformational changes mediated by extracellular loop 4 and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na+ affinity. This study firmly establishes missense, nonsense, frameshift and splice-site mutations in the GlyT2 gene as the second major cause of startle disease.

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<a title="" href="http://www.jbc.org/content/early/2012/06/29/jbc.M111.319244" target="_blank">doi: 10.1074/jbc.M111.319244 </a>
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<br/><strong>A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2 </strong><br/>


Cecilio Gimenez1, Gonzalo Perez-Siles1, Jaime Martinez-Villarreal1, Esther Arribas-Gonzalez1, Esperanza Jimenez1, Enrique Nunez1, Jaime de Juan-Sanz1, Enrique Fernandez-Sanchez1, Noemi Garcia-Tardon1, Ignacio Ibanez1, Valeria Romanelli2, Julian Nevado2, Victoria M. James3, Maya Topf4, Seo-Kyung Chung5, Rhys H. Thomas5, Lourdes R. Desviat1, Carmen Aragon1, Francisco Zafra1, Mark I. Rees5, Pablo Lapunzina2, Robert J. Harvey3 and Beatriz Lopez-Corcuera1,*

Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na+/Cl--dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation - p.Y705C (c.2114A&gt;G) in transmembrane domain 11 (TM11) - in eight individuals from Spain and the UK. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [3H]glycine transport, cell-surface expression and cysteine labeling assays. We found the introduced cysteine interacts with the cysteine pair C311-C320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression and inhibits transport function. Additionally, Y705C presents altered H+- and Zn2+-dependence of glycine transport that may affect the function of glycinergic neurotransmission in vivo.

<br/>来源：生物谷

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