{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:42:53Z","timestamp":1768506173295,"version":"3.49.0"},"posted":{"date-parts":[[2023,3,5]]},"group-title":"Physiology","reference-count":42,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Heterozygous germline variants in\n                  <jats:italic>ATP1A1<\/jats:italic>\n                  , the gene encoding the \u03b11 subunit of the Na\n                  <jats:sup>+<\/jats:sup>\n                  \/K\n                  <jats:sup>+<\/jats:sup>\n                  -ATPase (NKA), have been linked to diseases including primary hyperaldosteronism and the peripheral neuropathy Charcot-Marie-Tooth disease (CMT).\n                  <jats:italic>ATP1A1<\/jats:italic>\n                  variants that cause CMT induce loss-of-function of NKA. This heterodimeric (\u03b1\u03b2) enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na\n                  <jats:sup>+<\/jats:sup>\n                  and K\n                  <jats:sup>+<\/jats:sup>\n                  that are essential for electrical signaling and cell survival. Of the 4 catalytic subunit isoforms, \u03b11 is ubiquitously expressed and is the predominant paralog in peripheral axons. Human population sequencing datasets indicate strong negative selection against both missense and protein-null\n                  <jats:italic>ATP1A1<\/jats:italic>\n                  variants. To test whether haploinsufficiency generated by heterozygous protein-null alleles are sufficient to cause disease, we tested the neuromuscular characteristics of heterozygous\n                  <jats:italic>Atp1a1<\/jats:italic>\n                  <jats:sup>+\/-<\/jats:sup>\n                  knockout mice and their wildtype littermates, while also evaluating if exercise increased CMT penetrance. We found that\n                  <jats:italic>Atp1a1<\/jats:italic>\n                  <jats:sup>+\/-<\/jats:sup>\n                  mice were phenotypically normal up to 18 months of age. Consistent with the observations in mice, we report clinical phenotyping of a healthy adult human who lacks any clinical features of known\n                  <jats:italic>ATP1A1<\/jats:italic>\n                  -related diseases despite carrying a protein-null early truncation variant, p.Y148*. Taken together, these results suggest that a malfunctioning gene product is required for disease induction by\n                  <jats:italic>ATP1A1<\/jats:italic>\n                  variants and that if any pathology is associated with protein-null variants, they may display low penetrance or high age of onset.\n                <\/jats:p>","DOI":"10.1101\/2023.03.05.531165","type":"posted-content","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T16:05:21Z","timestamp":1678205121000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>ATP1A1<\/i>\n                  -linked diseases require a malfunctioning protein product from one allele"],"prefix":"10.64898","author":[{"given":"Kerri","family":"Spontarelli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria C.","family":"Young","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Sweazey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandria","family":"Padro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeannie","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tulio","family":"Bueso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto M.","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jongyeol","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Katz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis","family":"Rossignol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clesson","family":"Turner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caralynn M.","family":"Wilczewski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George L.","family":"Maxwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Holmgren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy D.","family":"Bailoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sho T.","family":"Yano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6893-9765","authenticated-orcid":false,"given":"Pablo","family":"Artigas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023030900051356000_2023.03.05.531165v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2550"},{"key":"2023030900051356000_2023.03.05.531165v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2716"},{"key":"2023030900051356000_2023.03.05.531165v1.3","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.01733"},{"key":"2023030900051356000_2023.03.05.531165v1.4","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.ajhg.2018.01.023","article-title":"Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2","volume":"102","year":"2018","journal-title":"Am J Hum Genet"},{"key":"2023030900051356000_2023.03.05.531165v1.5","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1002\/humu.23886","article-title":"ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease","volume":"40","year":"2019","journal-title":"Hum Mutat"},{"key":"2023030900051356000_2023.03.05.531165v1.6","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1111\/cge.13668","article-title":"Hereditary spastic paraplegia is a novel phenotype for germline de novo ATP1A1 mutation","volume":"97","year":"2020","journal-title":"Clin Genet"},{"key":"2023030900051356000_2023.03.05.531165v1.7","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.ajhg.2018.10.004","article-title":"Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability","volume":"103","year":"2018","journal-title":"Am J Hum Genet"},{"key":"2023030900051356000_2023.03.05.531165v1.8","doi-asserted-by":"crossref","first-page":"C394","DOI":"10.1152\/ajpcell.00059.2021","article-title":"Diseases caused by mutations in the Na(+)\/K(+) pump alpha1 gene ATP1A1","volume":"321","year":"2021","journal-title":"Am J Physiol Cell Physiol"},{"key":"2023030900051356000_2023.03.05.531165v1.9","doi-asserted-by":"crossref","unstructured":"F. 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