{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T03:42:11Z","timestamp":1771472531517,"version":"3.50.1"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>E193, a heterozygous truncating mutation in the human transcription cofactor Eyes absent 4 (Eya4), causes hearing impairment followed by dilative cardiomyopathy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              In this study, we first show Eya4 and E193 alter the expression of p27\n              <jats:sup>\n                <jats:italic>kip1<\/jats:italic>\n              <\/jats:sup>\n              in vitro, suggesting Eya4 is a negative regulator of p27. Next, we generated transgenic mice with cardiac-specific overexpression of Eya4 or E193. Luciferase and chromatin immunoprecipitation assays confirmed Eya4 and E193 bind and regulate p27 expression in a contradictory manner. Activity and phosphorylation status of the downstream molecules casein kinase-2\u03b1 and histone deacetylase 2 were significantly elevated in Eya4- but significantly reduced in E193-overexpressing animals compared with wild-type littermates. Magnetic resonance imaging and hemodynamic analysis indicate Eya4-overexpression results in an age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 animals develop onset of dilative cardiomyopathy as seen in human E193 patients. Both cardiac phenotypes were aggravated on pressure overload. Finally, we identified a new heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein as seen with E193.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Our results implicate Eya4\/Six1 regulates normal cardiac function via p27\/casein kinase-2\u03b1\/histone deacetylase 2 and indicate that mutations within this transcriptional complex and signaling cascade lead to the development of cardiomyopathy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.115.001134","type":"journal-article","created":{"date-parts":[[2015,10,24]],"date-time":"2015-10-24T02:38:41Z","timestamp":1445654321000},"page":"752-764","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Eya4 Induces Hypertrophy via Regulation of p27\n            <sup>kip1<\/sup>"],"prefix":"10.1161","volume":"8","author":[{"given":"Tatjana","family":"Williams","sequence":"first","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moritz","family":"Hundertmark","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Nordbeck","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Voll","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula Anahi","family":"Arias-Loza","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Oppelt","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"M\u00fchlfelder","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"Schraut","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ines","family":"Elsner","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Czolbe","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lea","family":"Seidlmayer","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britta","family":"Heinze","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Hahner","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Heinze","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jost","family":"Sch\u00f6nberger","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Jakob","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Ritter","sequence":"additional","affiliation":[{"name":"From the Department of Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (T.W., M.H., P.N., P.A.A.-L., D.O., M.M., S.S., I.E., M.C., L.S., B.H., S.H., J.S., O.R.); Comprehensive Heart Failure Center Wuerzburg, Wuerzburg, Germany (T.W., M.C., O.R.); Experimental Physics V, University Wuerzburg, Wuerzburg, Germany (P.N., S.V., P.J.); DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg, Germany (K.H.); and Department of Cardiology and Pneumology, Medical..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31860"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0126602"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31793"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/BF03402171","article-title":"A 4-bp insertion in the eya-homologous region (eyaHR) of EYA4 causes hearing impairment in a Hungarian family linked to DFNA10.","volume":"8","author":"Pfister M","year":"2002","unstructured":"Pfister M, T\u00f3th T, Thiele H, Haack B, Blin N, Zenner HP, et al.. 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