Cone-rod dystrophy (CORD) is an inherited retinal degenerative disease characterized by progressive loss of cone and rod photoreceptors. Although several genes have been reported to cause autosomal dominant CORD (adCORD), the genetic causes of adCORD have not been fully elucidated. Here, we identified the ATP1A3 gene, encoding the α3 subunit of Na+, K+-ATPase, as a novel gene associated with adCORD. Using whole-exome sequencing (WES), we found a candidate mutation of ATP1A3 that co-segregated with the disease in an analysis of two affected patients and one healthy relative in an adCORD family. According to our RNA-seq data, we demonstrated that the Atp1a3 mRNA level was extremely high in the murine retina. Overexpression of mutant ATP1A3 in vitro led to a reduced oxygen consumption rate (OCR), reflecting the limited mitochondrial reserve capacity. Furthermore, we generated transgenic mice expressing the ATP1A3 cDNA with patient variant and found decreased electroretinogram (ERG) responses. Moreover, the mutant ATP1A3 is highly expressed in photoreceptor inner segment, where mitochondria are enriched. These results suggest that the ATP1A3 mutation is a new genetic cause responsible for adCORD and indicate that ATP1A3 plays an important role in retinal function.

中文翻译：

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ATP1A3突变是常染色体显性圆锥杆营养不良的候选原因。

视锥细胞营养不良（CORD）是一种遗传性视网膜变性疾病，其特征是视锥细胞和视杆感光细胞逐渐丧失。尽管已经报道了几种基因导致常染色体显性CORD（adCORD），但尚未完全阐明adCORD的遗传原因。在这里，我们确定了编码Na +，K + -ATPase的α3亚基的ATP1A3基因，它是与adCORD相关的新基因。使用全外显子组测序（WES），在对adCORD家族的两名受影响患者和一名健康亲戚的分析中，我们发现了与该疾病共分离的ATP1A3候选突变。根据我们的RNA-seq数据，我们证明了鼠视网膜中Atp1a3 mRNA的水平非常高。突变型ATP1A3在体外的过表达导致降低的耗氧率（OCR），反映了有限的线粒体储备能力。此外，我们生成了带有患者变体的表达ATP1A3 cDNA的转基因小鼠，并发现视网膜电图（ERG）响应降低。此外，突变体ATP1A3在线粒体富集的感光器内部片段中高表达。这些结果表明，ATP1A3突变是引起adCORD的新遗传原因，表明ATP1A3在视网膜功能中起重要作用。