{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T11:12:55Z","timestamp":1769253175252,"version":"3.49.0"},"posted":{"date-parts":[[2024,1,17]]},"group-title":"Genetic and Genomic Medicine","reference-count":34,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene,\n                  <jats:italic>ACTN2<\/jats:italic>\n                  , have been shown to cause distal myopathy.\n                  <jats:italic>ACTN2<\/jats:italic>\n                  , a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. New\n                  <jats:italic>ACTN2<\/jats:italic>\n                  variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations in\n                  <jats:italic>ACTN2<\/jats:italic>\n                  -related diseases, actininopathies, persists.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>The objective of the study is to characterize the pathomechanisms underlying actininopathies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Functional characterization in C2C12 cell models of several\n                    <jats:italic>ACTN2<\/jats:italic>\n                    variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>\n                    The results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants in\n                    <jats:italic>ACTN2<\/jats:italic>\n                    should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.01.17.23298671","type":"posted-content","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T20:00:15Z","timestamp":1705521615000},"source":"Crossref","is-referenced-by-count":2,"title":["Rare\n                  <i>ACTN2<\/i>\n                  Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7050-8688","authenticated-orcid":false,"given":"Johanna","family":"Ranta-aho","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin J.","family":"Felice","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Per 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