Rea Ruth, Tijssen Marina A, Herd Colin, Frants Rune R, Kullmann Dimitri M
Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
Eur J Neurosci. 2002 Jul;16(2):186-96. doi: 10.1046/j.1460-9568.2002.02054.x.
The human disease hyperekplexia is characterized by excessive startle reactions to auditory and cutaneous stimuli. In its familial form, hyperekplexia has been associated with both dominant and recessive mutations of the GLRA1 gene encoding the glycine receptor alpha1 subunit (GlyRalpha1), which mediates inhibitory transmission in the spinal cord and brainstem. Here we have examined the functional consequences of two amino acid substitutions found in a compound heterozygous family, R252H and R392H, to investigate the mechanisms determining this inheritance pattern. When expressed in Xenopus laevis oocytes, both mutations were non-functional. Neither mutant affected the electrophysiological properties of wild type GlyRalpha1 when co-expressed. We introduced a green fluorescent protein tag to mutant subunits and found that both mutant proteins were detectable. Evidence that subcellular localization differed from wild type was significant for one of the mutants. Thus, an effective loss of functional GlyRalpha1-mediated current underlies hyperekplexia in this family, whereas a partial loss is asymptomatic.
人类疾病惊吓症的特征是对听觉和皮肤刺激产生过度的惊吓反应。在其家族形式中，惊吓症与编码甘氨酸受体α1亚基（GlyRα1）的GLRA1基因的显性和隐性突变有关，该亚基介导脊髓和脑干中的抑制性传递。在这里，我们研究了在一个复合杂合子家族中发现的两个氨基酸取代R252H和R392H的功能后果，以探究决定这种遗传模式的机制。当在非洲爪蟾卵母细胞中表达时，这两种突变均无功能。共表达时，两种突变体均未影响野生型GlyRα1的电生理特性。我们给突变亚基引入了绿色荧光蛋白标签，发现两种突变蛋白均可检测到。对于其中一个突变体而言，亚细胞定位不同于野生型这一证据具有重要意义。因此，在这个家族中，功能性GlyRα1介导的电流有效丧失是惊吓症的基础，而部分丧失则无症状。
