Document Detail

Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy.
MedLine Citation:
PMID:  23314057     Owner:  NLM     Status:  MEDLINE    
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.
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; Research Support, Non-U.S. Gov't     Date:  2013-01-13
Journal Detail:
Title:  Nature medicine     Volume:  19     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-07     Completed Date:  2013-04-17     Revised Date:  2014-07-03    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  193-201     Citation Subset:  IM    
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MeSH Terms
Amino Acid Sequence
Cardiomyopathies / etiology*,  genetics
HEK293 Cells
Heart / embryology
Heart Ventricles* / embryology
Molecular Sequence Data
Protein Multimerization
Receptors, Notch / physiology*
Signal Transduction / physiology*
Ubiquitin-Protein Ligases / genetics*,  physiology
Reg. No./Substance:
0/Receptors, Notch; EC ligase, human; EC Ligases
Comment In:
Nat Med. 2013 Feb;19(2):133-4   [PMID:  23389606 ]

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