A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve
Background: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...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/193600 |
| Acceso en línea: | https://hdl.handle.net/2445/193600 |
| Access Level: | acceso abierto |
| Palabra clave: | Miocardiopaties Malalties hereditàries Vàlvules cardíaques Myocardiopathies Genetic diseases Heart valves |
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A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve |
| title |
A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve |
| spellingShingle |
A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve Siguero Álvarez, Marcos Miocardiopaties Malalties hereditàries Vàlvules cardíaques Myocardiopathies Genetic diseases Heart valves |
| title_short |
A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve |
| title_full |
A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve |
| title_fullStr |
A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve |
| title_full_unstemmed |
A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve |
| title_sort |
A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve |
| dc.creator.none.fl_str_mv |
Siguero Álvarez, Marcos Salguero Jiménez, Alejandro Grego Bessa, Joaquim Barrera, Jorge de la Macgrogan, Donal Prados, Belén Sánchez Sáez, Fernando Piñeiro Sabarís, Rebeca Felipe Medina, Natalia Torroja, Carlos Gómez, Manuel José Sabater Molina, María Escribá, Rubén Richaud-Patin, Yvonne Iglesias García, Olalla Sbroggio, Mauro Callejas, Sergio O’regan, Declan P. Mcgurk, Kathryn A. Dopazo, Ana Giovinazzo, Giovanna Ibañez, Borja Monserrat, Lorenzo Pérez Pomares, José María Sánchez Cabo, Fátima Pendas, Alberto M. Raya Chamorro, Ángel Gimeno Blanes, Juan R. Pompa, José Luis de la |
| author |
Siguero Álvarez, Marcos |
| author_facet |
Siguero Álvarez, Marcos Salguero Jiménez, Alejandro Grego Bessa, Joaquim Barrera, Jorge de la Macgrogan, Donal Prados, Belén Sánchez Sáez, Fernando Piñeiro Sabarís, Rebeca Felipe Medina, Natalia Torroja, Carlos Gómez, Manuel José Sabater Molina, María Escribá, Rubén Richaud-Patin, Yvonne Iglesias García, Olalla Sbroggio, Mauro Callejas, Sergio O’regan, Declan P. Mcgurk, Kathryn A. Dopazo, Ana Giovinazzo, Giovanna Ibañez, Borja Monserrat, Lorenzo Pérez Pomares, José María Sánchez Cabo, Fátima Pendas, Alberto M. Raya Chamorro, Ángel Gimeno Blanes, Juan R. Pompa, José Luis de la |
| author_role |
author |
| author2 |
Salguero Jiménez, Alejandro Grego Bessa, Joaquim Barrera, Jorge de la Macgrogan, Donal Prados, Belén Sánchez Sáez, Fernando Piñeiro Sabarís, Rebeca Felipe Medina, Natalia Torroja, Carlos Gómez, Manuel José Sabater Molina, María Escribá, Rubén Richaud-Patin, Yvonne Iglesias García, Olalla Sbroggio, Mauro Callejas, Sergio O’regan, Declan P. Mcgurk, Kathryn A. Dopazo, Ana Giovinazzo, Giovanna Ibañez, Borja Monserrat, Lorenzo Pérez Pomares, José María Sánchez Cabo, Fátima Pendas, Alberto M. Raya Chamorro, Ángel Gimeno Blanes, Juan R. Pompa, José Luis de la |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Miocardiopaties Malalties hereditàries Vàlvules cardíaques Myocardiopathies Genetic diseases Heart valves |
| topic |
Miocardiopaties Malalties hereditàries Vàlvules cardíaques Myocardiopathies Genetic diseases Heart valves |
| description |
Background: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. Methods:We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense MIB1 mutation that are both found in LVNC families. We also generated mice separately carrying these MIB1 mutations plus 5 additional cosegregating variants in the ASXL3, APCDD1, TMX3, CEP192, and BCL7A 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-derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot. Results:Mice homozygous for the MIB1 nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous MIB1 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 ASXL3, APCDD1, TMX3, CEP192, and BCL7A cosegregating with the MIB1 mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding Mib1 backgrounds, triple heterozygous Mib1 Apcdd1 Asxl3 mice showed LVNC, whereas quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a 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-derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation. Conclusions: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. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2023 2023 2023 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion |
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article |
| status_str |
acceptedVersion |
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https://hdl.handle.net/2445/193600 |
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https://hdl.handle.net/2445/193600 |
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Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Versió postprint del document publicat a: https://doi.org/10.1161/CIRCULATIONAHA.121.058767 Circulation, 2023, vol. 147, num. 1, p. 47-65 https://doi.org/10.1161/CIRCULATIONAHA.121.058767 |
| dc.rights.none.fl_str_mv |
(c) American Heart Association, Inc., 2023 info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
(c) American Heart Association, Inc., 2023 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
19 p. application/pdf |
| dc.publisher.none.fl_str_mv |
Ovid Technologies (Wolters Kluwer Health) |
| publisher.none.fl_str_mv |
Ovid Technologies (Wolters Kluwer Health) |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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1869422451779174400 |
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A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic ValveSiguero Álvarez, MarcosSalguero Jiménez, AlejandroGrego Bessa, JoaquimBarrera, Jorge de laMacgrogan, DonalPrados, BelénSánchez Sáez, FernandoPiñeiro Sabarís, RebecaFelipe Medina, NataliaTorroja, CarlosGómez, Manuel JoséSabater Molina, MaríaEscribá, RubénRichaud-Patin, YvonneIglesias García, OlallaSbroggio, MauroCallejas, SergioO’regan, Declan P.Mcgurk, Kathryn A.Dopazo, AnaGiovinazzo, GiovannaIbañez, BorjaMonserrat, LorenzoPérez Pomares, José MaríaSánchez Cabo, FátimaPendas, Alberto M.Raya Chamorro, ÁngelGimeno Blanes, Juan R.Pompa, José Luis de laMiocardiopatiesMalalties hereditàriesVàlvules cardíaquesMyocardiopathiesGenetic diseasesHeart valvesBackground: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. Methods:We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense MIB1 mutation that are both found in LVNC families. We also generated mice separately carrying these MIB1 mutations plus 5 additional cosegregating variants in the ASXL3, APCDD1, TMX3, CEP192, and BCL7A 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-derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot. Results:Mice homozygous for the MIB1 nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous MIB1 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 ASXL3, APCDD1, TMX3, CEP192, and BCL7A cosegregating with the MIB1 mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding Mib1 backgrounds, triple heterozygous Mib1 Apcdd1 Asxl3 mice showed LVNC, whereas quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a 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-derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation. Conclusions: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.Ovid Technologies (Wolters Kluwer Health)2023202320222023info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion19 p.application/pdfhttps://hdl.handle.net/2445/193600Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1161/CIRCULATIONAHA.121.058767Circulation, 2023, vol. 147, num. 1, p. 47-65https://doi.org/10.1161/CIRCULATIONAHA.121.058767(c) American Heart Association, Inc., 2023info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1936002026-05-29T05:05:01Z |
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15,812429 |