The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p.P600R substitution causes demyelinating Charcot–Marie–Tooth disease

Background Charcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous group of inherited neuropathies. Monoallelic pathogenic variants in ATP1A1 were associated with axonal and intermediate CMT. ATP1A1 encodes for the catalytic α1 subunit of the Na + / K + ATPase. Besides neurop...

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Bibliographic Details
Published in:	Journal of neurology Vol. 270; no. 5; pp. 2576 - 2590
Main Authors:	Cinarli Yuksel, Feride, Nicolaou, Paschalis, Spontarelli, Kerri, Dohrn, Maike F., Rebelo, Adriana P., Koutsou, Pantelitsa, Georghiou, Anthi, Artigas, Pablo, Züchner, Stephan L., Kleopa, Kleopas A., Christodoulou, Kyproula
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-05-2023 Springer Nature B.V
Subjects:	Adenosine Triphosphatases - genetics Blood Cell viability Charcot-Marie-Tooth disease Charcot-Marie-Tooth Disease - genetics Charcot-Marie-Tooth Disease - pathology Demyelination DNA sequencing Electrophysiology Gene expression Genetics Genomes Genomics Humans Hypomagnesemia Intellectual disabilities Kidneys Medicine Medicine & Public Health mRNA Mutation Na+/K+-exchanging ATPase Neurology Neuroradiology Neurosciences Oocytes Original Communication Ouabain Pathogenicity Peripheral neuropathy Phenotype Phenotypes Proteins Proteins - genetics Sodium-Potassium-Exchanging ATPase - genetics Software Spastic paraplegia Xenopus Na Expression ATPase Electrophysiology Charcot–Marie–Tooth ATP1A1 K Ouabain survival assay Na+/K+ ATPase
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Summary:	Background Charcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous group of inherited neuropathies. Monoallelic pathogenic variants in ATP1A1 were associated with axonal and intermediate CMT. ATP1A1 encodes for the catalytic α1 subunit of the Na + / K + ATPase. Besides neuropathy, other associated phenotypes are spastic paraplegia, intellectual disability, and renal hypomagnesemia. We hereby report the first demyelinating CMT case due to a novel ATP1A1 variant. Methods Whole-exome sequencing on the patient’s genomic DNA and Sanger sequencing to validate and confirm the segregation of the identified p.P600R ATP1A1 variation were performed. To evaluate functional effects, blood-derived mRNA and protein levels of ATP1A1 and the auxiliary β1 subunit encoded by ATP1B1 were investigated. The ouabain-survival assay was performed in transfected HEK cells to assess cell viability, and two-electrode voltage clamp studies were performed in Xenopus oocytes. Results The variant was absent in the local and global control datasets, falls within a highly conserved protein position, and is in a missense-constrained region. The expression levels of ATP1A1 and ATP1B1 were significantly reduced in the patient compared to healthy controls. Electrophysiology indicated that ATP1A1 p.P600R injected Xenopus oocytes have reduced Na + / K + ATPase function. Moreover, HEK cells transfected with a construct encoding ATP1A1 p.P600R harbouring variants that confers ouabain insensitivity displayed a significant decrease in cell viability after ouabain treatment compared to the wild type, further supporting the pathogenicity of this variant. Conclusion Our results further confirm the causative role of ATP1A1 in peripheral neuropathy and broaden the mutational and phenotypic spectrum of ATP1A1 -associated CMT.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	0340-5354 1432-1459
DOI:	10.1007/s00415-023-11581-w