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Charcot-Marie-Tooth (CMT) disease comprises a group of inherited peripheral neuropathies caused by pathogenic variants in various genes, including ATP1A1. This gene encodes the ubiquitous α1 subunit of the sodium pump that generates the Na + and K + gradients that are essential for neuronal survival and excitability. We present the clinical cases of 2 unrelated patients with the same ATP1A1 variant causing dominant intermediate CMT disease and the functional characterization of the variant in the heterologous expression system.
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The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p.P600R substitution causes demyelinating Charcot–Marie–Tooth disease
Abstract BackgroundCharcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous group of inherited neuropathies. Monoallelic pathogenic variants inATP1A1were associated with axonal and intermediate CMT.ATP1A1encodes 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 novelATP1A1variant. MethodsWhole-exome sequencing on the patient’s genomic DNA and Sanger sequencing to validate and confirm the segregation of the identified p.P600RATP1A1variation were performed. To evaluate functional effects, blood-derived mRNA and protein levels ofATP1A1and the auxiliary β1 subunit encoded byATP1B1were 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. ResultsThe 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 thatATP1A1p.P600Rinjected Xenopus oocytes have reduced Na+/ K+ATPase function. Moreover, HEK cells transfected with a construct encodingATP1A1p.P600Rharbouring 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. ConclusionOur results further confirm the causative role ofATP1A1in peripheral neuropathy and broaden the mutational and phenotypic spectrum ofATP1A1-associated CMT.
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- Award ID(s):
- 2003251
- PAR ID:
- 10395354
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- Journal of Neurology
- Volume:
- 270
- Issue:
- 5
- ISSN:
- 0340-5354
- Page Range / eLocation ID:
- p. 2576-2590
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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