{"doi":"10.1161/circulationaha.122.059688","title":"Pathogenesis of Cardiomyopathy Caused by Variants in <i>ALPK3</i> , an Essential Pseudokinase in the Cardiomyocyte Nucleus and Sarcomere","abstract":"Background: ALPK3 encodes α-kinase 3, a muscle-specific protein of unknown function. ALPK3 loss-of-function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults, but the molecular functions of ALPK3 remain poorly understood. Methods: We explored the putative kinase activity of ALPK3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell–derived cardiomyocytes, mice, and human patient tissues. Results: Multiple sequence alignment of all human α-kinase domains and their orthologs revealed 4 conserved residues that were variant only in ALPK3, demonstrating evolutionary divergence of the ALPK3 α-kinase domain sequence. Phosphoproteomic evaluation of both ALPK3 kinase domain inhibition and overexpression failed to detect significant changes in catalytic activity, establishing ALPK3 as a pseudokinase. Investigations into alternative functions revealed that ALPK3 colocalized with myomesin proteins (MYOM1, MYOM2) at both the nuclear envelope and the sarcomere M-band. ALPK3 loss-of-function variants caused myomesin proteins to mislocalize and also dysregulated several additional M-band proteins involved in sarcomere protein turnover, which ultimately impaired cardiomyocyte structure and function. Conclusions: ALPK3 is an essential cardiac pseudokinase that inserts in the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes mislocalization of myomesins, critical force-buffering proteins in cardiomyocytes, and also dysregulates M-band proteins necessary for sarcomere protein turnover. We conclude that ALPK3 cardiomyopathy induces ventricular dilatation caused by insufficient myomesin-mediated force buffering and hypertrophy by impairment of sarcomere proteostasis.","journal":"Circulation","year":2022,"id":239369,"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":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9675,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":65133,"name":"Hiroko Wakimoto","orcid":"0000-0003-0225-6424","position":1,"is_corresponding":false},{"id":136624,"name":"Joao A. Paulo","orcid":"0000-0002-4291-413X","position":2,"is_corresponding":false},{"id":607020,"name":"Qi Zhang","orcid":"0000-0003-1121-8817","position":3,"is_corresponding":false},{"id":65099,"name":"Daniel Reichart","orcid":"0000-0002-8559-5888","position":4,"is_corresponding":false},{"id":232943,"name":"Christopher N. Toepfer","orcid":"0000-0003-4671-2030","position":5,"is_corresponding":false},{"id":232367,"name":"Arun Sharma","orcid":"0000-0002-0607-5455","position":6,"is_corresponding":false},{"id":319264,"name":"Angela C. Tai","orcid":null,"position":7,"is_corresponding":false},{"id":234513,"name":"Mingyue Lun","orcid":null,"position":8,"is_corresponding":false},{"id":5570,"name":"Joshua M. Gorham","orcid":"0000-0001-5969-4690","position":9,"is_corresponding":false},{"id":251041,"name":"Steven R. DePalma","orcid":"0000-0002-0381-5016","position":10,"is_corresponding":false},{"id":107041,"name":"Steven P. Gygi","orcid":"0000-0001-7626-0034","position":11,"is_corresponding":false},{"id":5584,"name":"Jonathan G. Seidman","orcid":"0000-0002-9082-3566","position":12,"is_corresponding":false},{"id":5583,"name":"Christine E. Seidman","orcid":"0000-0001-6380-1209","position":13,"is_corresponding":false},{"id":234511,"name":"Radhika Agarwal","orcid":null,"position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T00:22:36.865157Z","pmid":"36321451","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":[]}