2. Academic Validation
  3. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy

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

  • Nat Med. 2013 Feb;19(2):193-201. doi: 10.1038/nm.3046.
Guillermo Luxán 1,  Jesús C Casanova,  Beatriz Martínez-Poveda,  Belén Prados,  Gaetano D'Amato,  Donal MacGrogan,  Alvaro Gonzalez-Rajal,  David Dobarro,  Carlos Torroja,  Fernando Martinez,  José Luis Izquierdo-García,  Leticia Fernández-Friera,  María Sabater-Molina,  Young-Y Kong,  Gonzalo Pizarro,  Borja Ibañez,  Constancio Medrano,  Pablo García-Pavía,  Juan R Gimeno,  Lorenzo Monserrat,  Luis J Jiménez-Borreguero,  José Luis de la Pompa
Affiliations

Affiliation

  • 1 Program of Cardiovascular Developmental Biology, Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
PMID: 23314057 DOI: 10.1038/nm.3046
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.

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