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Open Access 04-02-2023 | Original Communication

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

Authors: Feride Cinarli Yuksel, Paschalis Nicolaou, Kerri Spontarelli, Maike F. Dohrn, Adriana P. Rebelo, Pantelitsa Koutsou, Anthi Georghiou, Pablo Artigas, Stephan L. Züchner, Kleopas A. Kleopa, Kyproula Christodoulou

Published in: Journal of Neurology | Issue 5/2023

Abstract

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.

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Title: The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p.P600R substitution causes demyelinating Charcot–Marie–Tooth disease
Authors: Feride Cinarli Yuksel
Paschalis Nicolaou
Kerri Spontarelli
Maike F. Dohrn
Adriana P. Rebelo
Pantelitsa Koutsou
Anthi Georghiou
Pablo Artigas
Stephan L. Züchner
Kleopas A. Kleopa
Kyproula Christodoulou
Publication date: 04-02-2023
Publisher: Springer Berlin Heidelberg
Published in: Journal of Neurology / Issue 5/2023
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-023-11581-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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