Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABA_A receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α₃-subunit of the GABA_A receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH₂-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α₃-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.

中文翻译：

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罕见的GABRA3变异与癫痫发作，脑病和畸形特征有关

遗传性癫痫病是由一系列不同基因的突变引起的，其中许多基因编码离子通道，受体或转运蛋白。尽管近年来检测到的变体和基因的数量急剧增加，但也已经认识到多效作用，这表明具有不同严重程度的临床综合征是由单个基因，单个突变或表现出相似功能缺陷的不同突变引起的。因此，一些编码GABA _A受体亚基的基因已经与一系列良性至严重的癫痫病相关联，并且表明功能丧失是主要的相关发病机制。在这里，我们确定了六个变体在GABRA3编码α ₃的GABA的亚基_甲受体。该基因位于Xq28染色体上，以前与人类疾病无关。在四个家庭和两个零星病例中发现了五个错义变异和一个微重复，这些病例表现出一系列癫痫发作类型，不同程度的智力残疾和发育迟缓，有时具有畸形特征或眼球震颤。这些变体大多与家族中的表型共分离，但并不完全分离，这表明在某些情况下外显力不完全，其他基因的参与或表型的存在。总体而言，男性受影响更为严重，与三名无症状的女性突变携带者相比，只有一名没有临床表型的男性。X染色体灭活研究无法解释女性的表型变异性。₂ -末端，一个在M2-M3接头和一个在α的M4跨膜区段₃亚基。在非洲爪蟾卵母细胞中进行的功能研究表明，与野生型受体相比，所有突变体的GABA诱发的阴离子电流都有可变但显着的降低。电流减少的程度与表型部分相关。微复制破坏了患病患者成纤维细胞中的GABRA3表达。总而言之，我们的研究结果表明，GABRA3中罕见的功能丧失变异体增加了癫痫，智力残疾/发育迟缓和畸形特征变化组合的风险，在某些家系中表现为X连锁遗传模式。