Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice
Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice
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DOI：
10.1016/j.ajhg.2008.07.008
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发表时间：
2008-08-08
影响因子：
9.8
通讯作者：
Puel, Jean-Luc
中科院分区：
文献类型：
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作者：
Ruel, Jerome;Emery, Sarah;Puel, Jean-Luc
常染色体显性感音神经性听力损失是遗传异质性的，其表型与老年性耳聋非常相似，老年性耳聋是人类中与衰老相关的最常见的感觉缺陷。我们已经确定了SLC 17 A8，它编码囊泡谷氨酸转运蛋白-3（VGLUT 3），作为DFNA 25的基因，DFNA 25是一种常染色体显性形式的进行性、高频非综合征性耳聋。在两个不相关的家族中，发现杂合错义突变c.632C -> T（p.A211V）与DFNA 25耳聋分离，但在267名对照中不存在。连锁不平衡分析表明，这些家系有一个遥远的共同祖先。A211残基在VGLUT 3中跨物种和在所有人VGLUT亚型（VGLUT 1 -3）中是保守的，表明重要的功能作用。在耳蜗中，VGLUT 3在感觉内毛细胞（IHC）的突触囊泡中积累谷氨酸，然后将其释放到神经末梢的受体上。Slc 17 a8外显子2有针对性缺失的小鼠缺乏听觉神经对声刺激的反应，尽管电刺激可以引起听觉脑干反应，并记录了强大的耳声发射。当在2周龄时通过膜电容测量探测时，在Slc 17 a8裸小鼠的IHC中，Ca 2+触发的突触囊泡周转是正常的。随后，感觉内毛细胞下方的传入突触、螺旋神经节神经元和外侧传出末梢的数量下降。带状突触剩余的3个月的年龄有一个正常的超微结构外观。我们的结论是耳聋Slc 17 a8缺陷小鼠是由于一个特定的缺陷囊泡谷氨酸的摄取和释放，VGLUT 3是必不可少的听觉编码在IHC突触。
Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a phenotype closely resembling presbycusis, the most common sensory defect associated with aging in humans. We have identified SLC17A8, which encodes the vesicular glutamate transporter-3 (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of progressive, high-frequency nonsyndromic deafness. In two unrelated families, a heterozygous missense mutation, c.632C -> T (p.A211V), was found to segregate with DFNA25 deafness and was not present in 267 controls. Linkage-disequilibrium analysis suggested that the families have a distant common ancestor. The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes (VGLUT1-3), suggesting an important functional role. In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals. Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded. Ca2+-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age. Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined. Ribbon synapses remaining by 3 months of age had a normal ultrastructural appearance. We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding at the IHC synapse.