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Monoallelic pathogenic variants in <jats:italic>ATP1A1<\/jats:italic> were associated with axonal and intermediate CMT. <jats:italic>ATP1A1<\/jats:italic> encodes for the catalytic \u03b11 subunit of the Na<jats:sup>+<\/jats:sup>\/ K<jats:sup>+<\/jats:sup> 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 <jats:italic>ATP1A1<\/jats:italic> variant.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Whole-exome sequencing on the patient\u2019s genomic DNA and Sanger sequencing to validate and confirm the segregation of the identified p.P600R <jats:italic>ATP1A1<\/jats:italic> variation were performed. To evaluate functional effects, blood-derived mRNA and protein levels of <jats:italic>ATP1A1<\/jats:italic> and the auxiliary \u03b21 subunit encoded by <jats:italic>ATP1B1<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>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 <jats:italic>ATP1A1<\/jats:italic><jats:sup>p.P600R<\/jats:sup> injected Xenopus oocytes have reduced Na<jats:sup>+<\/jats:sup>\/ K<jats:sup>+<\/jats:sup> ATPase function. Moreover, HEK cells transfected with a construct encoding <jats:italic>ATP1A1<\/jats:italic><jats:sup>p.P600R<\/jats:sup> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Our results further confirm the causative role of <jats:italic>ATP1A1<\/jats:italic> in peripheral neuropathy and broaden the mutational and phenotypic spectrum of <jats:italic>ATP1A1<\/jats:italic>-associated CMT.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00415-023-11581-w","type":"journal-article","created":{"date-parts":[[2023,2,4]],"date-time":"2023-02-04T10:03:12Z","timestamp":1675504992000},"page":"2576-2590","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p.P600R substitution causes demyelinating Charcot\u2013Marie\u2013Tooth disease"],"prefix":"10.1007","volume":"270","author":[{"given":"Feride","family":"Cinarli Yuksel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paschalis","family":"Nicolaou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerri","family":"Spontarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike F.","family":"Dohrn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana P.","family":"Rebelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pantelitsa","family":"Koutsou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthi","family":"Georghiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Artigas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan L.","family":"Z\u00fcchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kleopas A.","family":"Kleopa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-7594","authenticated-orcid":false,"given":"Kyproula","family":"Christodoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,4]]},"reference":[{"issue":"3","key":"11581_CR1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1159\/000314351","volume":"35","author":"P Nicolaou","year":"2010","unstructured":"Nicolaou P, Zamba-Papanicolaou E, Koutsou P, Kleopa KA, Georghiou A, Hadjigeorgiou G et al (2010) Charcot\u2013Marie\u2013Tooth disease in cyprus: epidemiological. 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