TY - JOUR
T1 - Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy
AU - Luxan, Guillermo
AU - Fernandez Casanova, Jesus
AU - Martinez Poveda, Beatriz
AU - Prados Pinto, Belen
AU - D'Amato, Gaetano
AU - MacGrogan, Donal
AU - Gonzalez-Rajal, Alvaro
AU - Dobarro, David
AU - Torroja, Carlos
AU - Martinez de Benito, Fernando
AU - Izquierdo-Garcia, Jose Luis
AU - Fernandez-Friera, Leticia America
AU - Sabater Molina, Maria
AU - Kong, Young-Y
AU - Pizarro, Gonzalo
AU - Ibanez Cabeza, Borja
AU - Medrano Lopez, Constancio
AU - Garcia-Pavia, Pablo
AU - Gimeno, Juan Ramon
AU - Monserrat Iglesias, Lorenzo
AU - Jimenez-Borreguero, Luis J
AU - Pompa, Jose Luis de la
PY - 2013
Y1 - 2013
N2 - 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.
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.
UR - http://www.nature.com/nm/journal/v19/n2/pdf/nm.3046.pdf
U2 - 10.1038/nm.3046
DO - 10.1038/nm.3046
M3 - Article
SN - 1078-8956
VL - 19
SP - 193
EP - 201
JO - Nature Medicine
JF - Nature Medicine
IS - 2
ER -
