{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T14:21:14Z","timestamp":1781360474771,"version":"3.54.1"},"reference-count":112,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2023,1,3]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis, and sporadic occurrence. These features have hampered disease modeling and mechanistic understanding. Here, we show that 2 structural cardiac diseases, left ventricular noncompaction (LVNC) and bicuspid aortic valve, can be caused by a set of inherited heterozygous gene mutations affecting the NOTCH ligand regulator MIB1 (MINDBOMB1) and cosegregating genes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense\n              <jats:italic>MIB1<\/jats:italic>\n              mutation that are both found in LVNC families. We also generated mice separately carrying these\n              <jats:italic>MIB1<\/jats:italic>\n              mutations plus 5 additional cosegregating variants in the\n              <jats:italic>ASXL3<\/jats:italic>\n              ,\n              <jats:italic>APCDD1<\/jats:italic>\n              ,\n              <jats:italic>TMX3, CEP192<\/jats:italic>\n              , and\n              <jats:italic>BCL7A<\/jats:italic>\n              genes identified in these LVNC families by whole exome sequencing. Histological, developmental, and functional analyses of these mouse models were carried out by echocardiography and cardiac magnetic resonance imaging, together with gene expression profiling by RNA sequencing of both selected engineered mouse models and human induced pluripotent stem cell\u2013derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Mice homozygous for the\n              <jats:italic>MIB1<\/jats:italic>\n              nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous\n              <jats:italic>MIB1<\/jats:italic>\n              missense allele leads to bicuspid aortic valve in a NOTCH-sensitized genetic background. These data suggest that development of LVNC is influenced by genetic modifiers present in affected families, whereas valve defects are highly sensitive to NOTCH haploinsufficiency. Whole exome sequencing of LVNC families revealed single-nucleotide gene variants of\n              <jats:italic>ASXL3<\/jats:italic>\n              ,\n              <jats:italic>APCDD1<\/jats:italic>\n              ,\n              <jats:italic>TMX3, CEP192<\/jats:italic>\n              , and\n              <jats:italic>BCL7A<\/jats:italic>\n              cosegregating with the\n              <jats:italic>MIB1<\/jats:italic>\n              mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding\n              <jats:italic>Mib1<\/jats:italic>\n              backgrounds, triple heterozygous\n              <jats:italic>Mib1 Apcdd1 Asxl3<\/jats:italic>\n              mice showed LVNC, whereas quadruple heterozygous\n              <jats:italic>Mib1 Cep192 Tmx3;Bcl7a<\/jats:italic>\n              mice developed bicuspid aortic valve and other valve-associated defects. Biochemical analysis suggested interactions between CEP192, BCL7A, and NOTCH. Gene expression profiling of mutant mouse hearts and human induced pluripotent stem cell\u2013derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>These findings reveal a shared genetic substrate underlying LVNC and bicuspid aortic valve in which MIB1-NOTCH variants plays a crucial role in heterozygous combination with cosegregating genetic modifiers.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.121.058767","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T09:01:08Z","timestamp":1667466068000},"page":"47-65","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve"],"prefix":"10.1161","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1945-0178","authenticated-orcid":true,"given":"Marcos","family":"Siguero-\u00c1lvarez","sequence":"first","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."},{"name":"Center for Chromosome Stability and Institut for Cellul\u00e6r og Molekyl\u00e6r Medicin, University of Copenhagen, Denmark (M.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6816-8983","authenticated-orcid":true,"given":"Alejandro","family":"Salguero-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-2346","authenticated-orcid":true,"given":"Joaquim","family":"Grego-Bessa","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8138-6093","authenticated-orcid":true,"given":"Jorge","family":"de la Barrera","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit (J.d.l.B., C.T., M.J.G., F.S.-C.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2808-8422","authenticated-orcid":true,"given":"Donal","family":"MacGrogan","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-5626","authenticated-orcid":true,"given":"Bel\u00e9n","family":"Prados","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."},{"name":"Pluripotent Cell Technology Unit (B.P., G.G.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3720-5355","authenticated-orcid":true,"given":"Fernando","family":"S\u00e1nchez-S\u00e1ez","sequence":"additional","affiliation":[{"name":"Molecular Mechanisms Program, Centro de Investigaci\u00f3n del C\u00e1ncer and Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer Universidad de Salamanca, Spain (F.S.-S., N.F.-M., A.M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4227-8484","authenticated-orcid":true,"given":"Rebeca","family":"Pi\u00f1eiro-Sabar\u00eds","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6975-2524","authenticated-orcid":true,"given":"Natalia","family":"Felipe-Medina","sequence":"additional","affiliation":[{"name":"Molecular Mechanisms Program, Centro de Investigaci\u00f3n del C\u00e1ncer and Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer Universidad de Salamanca, Spain (F.S.-S., N.F.-M., A.M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8914-3400","authenticated-orcid":true,"given":"Carlos","family":"Torroja","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit (J.d.l.B., C.T., M.J.G., F.S.-C.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4111-4835","authenticated-orcid":true,"given":"Manuel Jos\u00e9","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Genomics Unit (S.C., A.D.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain."},{"name":"Laboratorio de Cardiogen\u00e9tica, Instituto Murciano de Investigaci\u00f3n Biosanitaria, European Reference Networks and Unidad de Referencia-European Reference Networks Guard Heart de Cardiopatias Familiares, Hospital Universitario Virgen de la Arrixaca-Universidad de Murcia, El Palmar, Spain (M.S.-M., J.R.G.-B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1352-1748","authenticated-orcid":true,"given":"Mar\u00eda","family":"Sabater-Molina","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8072-8709","authenticated-orcid":true,"given":"Rub\u00e9n","family":"Escrib\u00e1","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Program, Bellvitge Institute for Biomedical Research, Program for Clinical Translation of Regenerative Medicine in Catalonia, Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine and Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats, Barcelona, Spain (R.E., I.R.-P., O.I.-G., A.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2293-4691","authenticated-orcid":true,"given":"Ivonne","family":"Richaud-Patin","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Program, Bellvitge Institute for Biomedical Research, Program for Clinical Translation of Regenerative Medicine in Catalonia, Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine and Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats, Barcelona, Spain (R.E., I.R.-P., O.I.-G., A.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7728-9207","authenticated-orcid":true,"given":"Olalla","family":"Iglesias-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Program, Bellvitge Institute for Biomedical Research, Program for Clinical Translation of Regenerative Medicine in Catalonia, Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine and Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats, Barcelona, Spain (R.E., I.R.-P., O.I.-G., A.R.)."},{"name":"Regenerative Medicine Program, Cima Universidad de Navarra, Navarra Institute for Health Research, Pamplona, Spain (O.I.-G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8266-661X","authenticated-orcid":true,"given":"Mauro","family":"Sbroggio","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3351-4940","authenticated-orcid":true,"given":"Sergio","family":"Callejas","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares and Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain (M.S.-A., A.S.-J., J.G.-B., D.M., B.P., R.P.-S., M.S., S.C.\u201a A.D.\u201a B.I., J.L.d.l.P.)."},{"name":"Genomics Unit (S.C., A.D.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0691-0270","authenticated-orcid":true,"given":"Declan P.","family":"O\u2019Regan","sequence":"additional","affiliation":[{"name":"Medical Research Council London Institute of Medical Sciences (D.P.O.\u201a K.A.M.), Imperial College London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5445-6906","authenticated-orcid":true,"given":"Kathryn A.","family":"McGurk","sequence":"additional","affiliation":[{"name":"Medical Research Council London Institute of Medical Sciences (D.P.O.\u201a K.A.M.), Imperial College London, United Kingdom."},{"name":"National Heart and Lung Institute (K.A.M.), Imperial College London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4910-1684","authenticated-orcid":true,"given":"Ana","family":"Dopazo","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development &amp; 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