{"doi":"10.1101/2023.03.05.531165","title":"<i>ATP1A1</i> -linked diseases require a malfunctioning protein product from one allele","abstract":"Abstract Heterozygous germline variants in ATP1A1 , the gene encoding the α1 subunit of the Na + /K + -ATPase (NKA), have been linked to diseases including primary hyperaldosteronism and the peripheral neuropathy Charcot-Marie-Tooth disease (CMT). ATP1A1 variants that cause CMT induce loss-of-function of NKA. This heterodimeric (αβ) enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na + and K + that are essential for electrical signaling and cell survival. Of the 4 catalytic subunit isoforms, α1 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 ATP1A1 variants. To test whether haploinsufficiency generated by heterozygous protein-null alleles are sufficient to cause disease, we tested the neuromuscular characteristics of heterozygous Atp1a1 +/- knockout mice and their wildtype littermates, while also evaluating if exercise increased CMT penetrance. We found that Atp1a1 +/- 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 ATP1A1 -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 ATP1A1 variants and that if any pathology is associated with protein-null variants, they may display low penetrance or high age of onset.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":403532,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":465231,"name":"Victoria C. Young","orcid":"0000-0002-4027-8694","position":1,"is_corresponding":false},{"id":687215,"name":"Ryan Sweazey","orcid":null,"position":2,"is_corresponding":false},{"id":1126629,"name":"Alexandria Padro","orcid":null,"position":3,"is_corresponding":false},{"id":933667,"name":"Jeannie K. Lee","orcid":"0000-0001-9907-6993","position":4,"is_corresponding":false},{"id":1126144,"name":"Tulio Bueso","orcid":"0000-0002-2196-1359","position":5,"is_corresponding":false},{"id":1126145,"name":"Roberto M. Hernandez","orcid":"0000-0001-9405-6213","position":6,"is_corresponding":false},{"id":1126146,"name":"Jong-Yeol Kim","orcid":"0009-0003-3983-3341","position":7,"is_corresponding":false},{"id":280951,"name":"Alexander Katz","orcid":"0000-0001-9706-9490","position":8,"is_corresponding":false},{"id":706525,"name":"Francis Rossignol","orcid":"0000-0002-8896-1468","position":9,"is_corresponding":false},{"id":648116,"name":"Clesson Turner","orcid":"0000-0001-7625-8022","position":10,"is_corresponding":false},{"id":595869,"name":"Caralynn M. Wilczewski","orcid":"0000-0003-0336-8815","position":11,"is_corresponding":false},{"id":885179,"name":"George L. Maxwell","orcid":null,"position":12,"is_corresponding":false},{"id":362145,"name":"Miguel Holmgren","orcid":"0000-0001-8285-4242","position":13,"is_corresponding":false},{"id":1126147,"name":"Jeremy D. Bailoo","orcid":"0000-0002-3767-2922","position":14,"is_corresponding":false},{"id":362142,"name":"Sho Yano","orcid":"0000-0002-4177-3064","position":15,"is_corresponding":false},{"id":465232,"name":"Pablo Artigas","orcid":"0000-0002-6893-9765","position":16,"is_corresponding":false},{"id":465230,"name":"Kerri Spontarelli","orcid":"0000-0002-5988-028X","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T01:20:36.280647Z","pmid":"37090550","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}