TY - JOUR 
A1 - Luxán, Guillermo
AU - Casanova, Jesús C.
AU - Martínez-Poveda, Beatriz
AU - Prados, Belén
AU - D'Amato, Gaetano
AU - MacGrogan, Donald
AU - González-Rajal, Álvaro
AU - Dobarro Pérez, David
AU - Torroja, Carlos
AU - Martínez, Fernando
AU - Izquierdo García, José Luis
AU - Fernández Friera, Leticia
AU - Sabater-Molina, María
AU - Kong, Young-Y
AU - Pizarro, Gonzalo
AU - Ibáñez, Borja
AU - Medrano, Constancio
AU - García Pavía, Pablo
AU - Gimeno, Juan R.
AU - Monserrat, Luis Lorenzo
AU - Jiménez-Borreguero, Luis J.
AU - Pompa, José Luis de la
T1 - Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy
Y1 - 2013
UR - http://hdl.handle.net/11268/2202
AB - 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.
KW - Genética humana
KW - Enfermedad cardiovascular
LA - eng
ER -