A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve.

Autor:	Siguero-Álvarez M; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.).; Center for Chromosome Stability and Institut for Cellulær og Molekylær Medicin, University of Copenhagen, Denmark (M.S.)., Salguero-Jiménez A; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.)., Grego-Bessa J; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.)., de la Barrera J; Bioinformatics Unit (J.d.l.B., C.T., M.J.G., F.S.-C.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain., MacGrogan D; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.)., Prados B; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.).; Pluripotent Cell Technology Unit (B.P., G.G.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain., Sánchez-Sáez F; Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer Universidad de Salamanca, Spain (F.S.-S., N.F.-M., A.M.P.)., Piñeiro-Sabarís R; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.)., Felipe-Medina N; Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer Universidad de Salamanca, Spain (F.S.-S., N.F.-M., A.M.P.)., Torroja C; Bioinformatics Unit (J.d.l.B., C.T., M.J.G., F.S.-C.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain., Gómez MJ; Genomics Unit (S.C., A.D.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.; Laboratorio de Cardiogenética, Instituto Murciano de Investigación 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.)., Sabater-Molina M; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.)., Escribá R; 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 Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (R.E., I.R.-P., O.I.-G., A.R.)., Richaud-Patin I; 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 Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (R.E., I.R.-P., O.I.-G., A.R.)., Iglesias-García O; 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 Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (R.E., I.R.-P., O.I.-G., A.R.).; Regenerative Medicine Program, Cima Universidad de Navarra, Navarra Institute for Health Research, Pamplona, Spain (O.I.-G.)., Sbroggio M; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.)., Callejas S; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.).; Genomics Unit (S.C., A.D.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain., O'Regan DP; Medical Research Council London Institute of Medical Sciences (D.P.O.' K.A.M.), Imperial College London, United Kingdom., McGurk KA; Medical Research Council London Institute of Medical Sciences (D.P.O.' K.A.M.), Imperial College London, United Kingdom.; National Heart and Lung Institute (K.A.M.), Imperial College London, United Kingdom., Dopazo A; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.).; Genomics Unit (S.C., A.D.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain., Giovinazzo G; Pluripotent Cell Technology Unit (B.P., G.G.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain., Ibañez B; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.).; Translational Laboratory (B.I.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.; Cardiology Department, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz Hospital, Madrid, Spain (B.I.)., Monserrat L; Instituto de Investigación Biomédica de A Coruña and Departamento Científico, Health in Code S.L., A Coruña, Spain (L.M.)., Pérez-Pomares JM; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.).; Department of Animal Biology, Faculty of Sciences, Instituto de Investigación Biomédica de Málaga and Centro Andaluz de Nanomedicina y Biotecnología, Universidad de Málaga, Spain (J.M.P.-P.)., Sánchez-Cabo F; Bioinformatics Unit (J.d.l.B., C.T., M.J.G., F.S.-C.), Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain., Pendas AM; Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer Universidad de Salamanca, Spain (F.S.-S., N.F.-M., A.M.P.)., Raya A; 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 Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (R.E., I.R.-P., O.I.-G., A.R.)., Gimeno-Blanes JR; Laboratorio de Cardiogenética, Instituto Murciano de Investigación 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.)., de la Pompa JL; Intercellular Signaling in Cardiovascular Development & 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.' A.D.' B.I., J.L.d.l.P.).
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2023 Jan 03; Vol. 147 (1), pp. 47-65. Date of Electronic Publication: 2022 Nov 03.
DOI:	10.1161/CIRCULATIONAHA.121.058767
Abstrakt:	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.
Databáze:	MEDLINE
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