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Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy.
MedLine Citation:
PMID:  23314057     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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:
Guillermo Luxán; 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
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-13
Journal Detail:
Title:  Nature medicine     Volume:  -     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Program of Cardiovascular Developmental Biology, Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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