Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy

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dc.contributor.author Luxán, Guillermo spa
dc.contributor.author Casanova, Jesús C. spa
dc.contributor.author Martínez-Poveda, Beatriz spa
dc.contributor.author Prados, Belén spa
dc.contributor.author D'Amato, Gaetano spa
dc.contributor.author MacGrogan, Donald spa
dc.contributor.author González-Rajal, Álvaro spa
dc.contributor.author Dobarro, David spa
dc.contributor.author Torroja, Carlos spa
dc.contributor.author Martínez, Fernando spa
dc.contributor.author Izquierdo García, José Luis spa
dc.contributor.author Fernández-Friera, Leticia spa
dc.contributor.author Sabater-Molina, María spa
dc.contributor.author Kong, Young-Y spa
dc.contributor.author Pizarro, Gonzalo spa
dc.contributor.author Ibáñez, Borja spa
dc.contributor.author Medrano, Constancio spa
dc.contributor.author García-Pavía, Pablo spa
dc.contributor.author Gimeno, Juan R. spa
dc.contributor.author Monserrat, Luis Lorenzo spa
dc.contributor.author Jiménez-Borreguero, Luis J. spa
dc.contributor.author Pompa, José Luis de la spa
dc.date.accessioned 2014-03-18T10:09:19Z
dc.date.available 2014-03-18T10:09:19Z
dc.date.issued 2013 spa
dc.identifier.citation Luxán, G., Casanova, J. C., Martínez-Poveda, B., Prados, B., D'Amato, G., MacGrogan, D., …, & Pompa, J. L. (2013). Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nature Medicine, 19(2), 193-201. spa
dc.identifier.uri http://hdl.handle.net/11268/2202
dc.description.abstract Left ventricular noncompaction (LVNC) causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction. spa
dc.language.iso eng spa
dc.title Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy spa
dc.type article spa
dc.description.impact 28.054 JCR (2013) Q1, 2/291 Biochemistry & molecular biology, 3/185 Cell biology, 1/122 Medicine, research & experimental spa
dc.identifier.doi 10.1038/nm.3046 spa
dc.rights.accessRights closedAccess en
dc.subject.unesco Genética humana spa
dc.subject.unesco Enfermedad cardiovascular spa
dc.peerreviewed Si spa

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