{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:13:46Z","timestamp":1790680426500,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Pediatric cardiomyopathies are a clinically and genetically heterogeneous group of heart muscle disorders associated with high morbidity and mortality. Although knowledge of the genetic basis of pediatric cardiomyopathy has improved considerably, the underlying cause remains elusive in a substantial proportion of cases.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy. Protein expression was assessed in patient samples, followed by an in vitro tail-anchored protein insertion assay and functional analyses in zebrafish.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We identified compound heterozygous variants in the highly conserved\n              <jats:italic>ASNA1<\/jats:italic>\n              gene (arsA arsenite transporter, ATP-binding, homolog), which encodes an ATPase required for post-translational membrane insertion of tail-anchored proteins. The c.913C&gt;T variant on the paternal allele is predicted to result in a premature stop codon p.(Gln305*), and likely explains the decreased protein expression observed in myocardial tissue and skin fibroblasts. The c.488T&gt;C variant on the maternal allele results in a valine to alanine substitution at residue 163 (p.Val163Ala). Functional studies showed that this variant leads to protein misfolding as well as less effective tail-anchored protein insertion. Loss of\n              <jats:italic>asna1<\/jats:italic>\n              in zebrafish resulted in reduced cardiac contractility and early lethality. In contrast to wild-type mRNA, injection of either mutant mRNA failed to rescue this phenotype.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Biallelic variants in\n              <jats:italic>ASNA1<\/jats:italic>\n              cause severe pediatric cardiomyopathy and early death. Our findings point toward a critical role of the tail-anchored membrane protein insertion pathway in vertebrate cardiac function and disease.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002507","type":"journal-article","created":{"date-parts":[[2019,9,17]],"date-time":"2019-09-17T18:00:30Z","timestamp":1568743230000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Biallelic Variants in\n            <i>ASNA1<\/i>\n            , Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy"],"prefix":"10.1161","volume":"12","author":[{"given":"Judith M.A.","family":"Verhagen","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myrthe","family":"van den Born","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herma C.","family":"van der Linde","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"G.J. Nikkels","sequence":"additional","affiliation":[{"name":"Department of Pathology (P.G.J.N.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob M.","family":"Verdijk","sequence":"additional","affiliation":[{"name":"Department of Pathology (R.M.V.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryann H.","family":"Kivlen","sequence":"additional","affiliation":[{"name":"Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, United Kingdom (M.H.K., R.S.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leontine M.A.","family":"van Unen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette F.","family":"Baas","sequence":"additional","affiliation":[{"name":"Department of Genetics (A.F.B.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henriette","family":"ter Heide","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology (H.t.H.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lennie","family":"van Osch-Gevers","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology (L.v.O.-G.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Hoogeveen-Westerveld","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna C.","family":"Herkert","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (J.C.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida M.","family":"Bertoli-Avella","sequence":"additional","affiliation":[{"name":"Centogene AG, Rostock (A.M.B.-A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon A.","family":"van Slegtenhorst","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja W.","family":"Wessels","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans W.","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hassel","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University Hospital Heidelberg, Germany (D.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.W.","family":"Hofstra","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramanujan S.","family":"Hegde","sequence":"additional","affiliation":[{"name":"Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, United Kingdom (M.H.K., R.S.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"van Hasselt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (P.M.v.H.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjakko J.","family":"van Ham","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.B.H.","family":"van de Laar","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (J.M.A.V., M.v.d.B., H.C.v.d.L., L.M.A.v.U., M.H.-W., M.A.v.S., M.W.W., F.W.V., R.M.W.H., T.J.v.H., I.M.B.H.v.d.L.), Erasmus MC, University Medical Center Rotterdam."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv727"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11886-013-0375-1"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309386"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ppedcard.2010.11.008"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.08.2171"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd4030011"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2018.9"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.01.036"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3226"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2010.07.010"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.06.017"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-169X.2008.01084.x"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(03)00207-7"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.106518"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.154468"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.12.031"},{"key":"e_1_3_4_18_2","volume-title":"The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio)","author":"Westerfield M","year":"2000","unstructured":"Westerfield, M. The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio). 4th ed. Eugene, OR: University of Oregon Press; 2000.","edition":"4"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22332"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08319"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah6130"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085033"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.06.025"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd3020013"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.179333"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-510x(03)00012-1"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.11.012"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfs119"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.15-18996"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP271437"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201593565"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao3099"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200608101"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.207829"}],"updated-by":[{"DOI":"10.1161\/hcg.0000000000000065","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T00:00:00Z","timestamp":1592265600000}}],"container-title":["Circulation: Genomic and Precision Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGEN.119.002507","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:35:30Z","timestamp":1715564130000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGEN.119.002507"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9]]},"references-count":33,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2019,9]]}},"alternative-id":["10.1161\/CIRCGEN.119.002507"],"URL":"https:\/\/doi.org\/10.1161\/circgen.119.002507","relation":{"correction":[{"id-type":"doi","id":"10.1161\/HCG.0000000000000065","asserted-by":"object"}]},"ISSN":["2574-8300"],"issn-type":[{"value":"2574-8300","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9]]},"assertion":[{"value":"2019-02-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-08-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-08-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e002507"}}