Abstract
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.
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The datasets generated during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors thank for all individuals examined in the investigation and supporting from the Specific Pathogen Free animal facility of Wenzhou Medical University.
Funding
This study was supported by the National Key Research and Development Program of China (2017YFA0105300), the National Natural Science Foundation of China (81970838), the Zhejiang Provincial Natural Science Foundation of China (LD18H120001LD).
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Z-BJ designed the whole study, recruited patients and provided financial support; G-HZ performed whole-exome analysis; G-HZ analyzed and interpreted the results; G-HZ, YM, M-LL performed animal experiments and analyzed data; G-HZ and Z-BJ wrote the manuscript.
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Zhou, GH., Ma, Y., Li, ML. et al. ATP1A3 mutation as a candidate cause of autosomal dominant cone-rod dystrophy. Hum Genet 139, 1391–1401 (2020). https://doi.org/10.1007/s00439-020-02182-y
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DOI: https://doi.org/10.1007/s00439-020-02182-y