title: Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy.
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.
authors: Program of Cardiovascular Developmental Biology, Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors: Guillermo
authors: G
authors: Luxán
authors: Jesús C
authors: JC
authors: Casanova
authors: Beatriz
authors: B
authors: Martínez-Poveda
authors: Belén
authors: B
authors: Prados
authors: Gaetano
authors: G
authors: D'Amato
authors: Donal
authors: D
authors: MacGrogan
authors: Alvaro
authors: A
authors: Gonzalez-Rajal
authors: David
authors: D
authors: Dobarro
authors: Carlos
authors: C
authors: Torroja
authors: Fernando
authors: F
authors: Martinez
authors: José Luis
authors: JL
authors: Izquierdo-García
authors: Leticia
authors: L
authors: Fernández-Friera
authors: María
authors: M
authors: Sabater-Molina
authors: Young-Y
authors: YY
authors: Kong
authors: Gonzalo
authors: G
authors: Pizarro
authors: Borja
authors: B
authors: Ibañez
authors: Constancio
authors: C
authors: Medrano
authors: Pablo
authors: P
authors: García-Pavía
authors: Juan R
authors: JR
authors: Gimeno
authors: Lorenzo
authors: L
authors: Monserrat
authors: Luis J
authors: LJ
authors: Jiménez-Borreguero
authors: José Luis
authors: JL
authors: de la Pompa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006321:Heart / Q000196:embryology; D006352:Heart Ventricles / Q000196:embryology; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D055503:Protein Multimerization; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology; D015027:Zebrafish
chemical_list: D051880:Receptors, Notch; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases