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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE71912 | GEO | 2015/08/10

SECONDARY ACCESSION(S): PRJNA292442

REPOSITORIES: GEO

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

Project description: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. RNA was isolated from the ventricles of 16 WT and 16 Mib1flox; CTnT-cre hearts at E14.5 and then pooled into four replicates.

2015-08-10 | E-GEOD-71912 | biostudies-arrayexpress

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Project description:The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis and sporadic occurrence. These features have hampered disease modelling and mechanistic understanding. Here, we show that two structural cardiac diseases, left ventricular non-compaction (LVNC) and bicuspid aortic valve (BAV), can be caused by a combined set of inherited heterozygous mutations. We used CRISPR-Cas9 gene editing to generate mice harboring two mutations in the NOTCH ligand regulator MINDBOMB1 identified in LVNC families. One Mib1 mutation causes LVNC only in heteroallelic combination with a conditional Mib1 allele, while the other leads to BAV in a NOTCH-sensitized genetic background. These data suggest that the LVNC phenotype may be influenced by genetic modifiers present in these families, while valve defects are very sensitive to NOTCH haploinsufficiency. Whole-exome sequencing revealed single-nucleotide variants in the ASXL3, APCDD1 and TMX3, CEP192 and BCL7A genes, co-segregating with the MIB1 mutations and LVNC. We generated mice harboring the orthologous variants in the corresponding Mib1 backgrounds. Triple heterozygous Mib1 Apcdd1 Asxl3 mutants show LVNC, while quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice show BAV and other valve-associated defects. Biochemical assays suggest interactions between CEP192, BCL7A and NOTCH. Gene profiling of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes reveals defective metabolic maturation. These findings provide evidence for a common genetic substrate for LVNC and BAV involving MIB1 and genetic modifiers

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

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Sequential Notch activation regulates ventricular chamber development

Project description:Ventricular chambers are essential for the rhythmic contraction and relaxation that occurs in every hearbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is still poorly understood. Here we show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation and later coordinates ventricular patterning and compaction with coronary vessel development to give rise to the mature chamber via a temporal sequence of ligand signalling determined by the glycosyltransferase Manic Fringe (Mfng). The early endocardial expression of Mfng favours Dll4-Notch1 signalling, Which induces trabeculation in the developing ventricle.Ventricular maturation and compaction in turn require Mfng and Dll4 downregulation in the endocardium, Which allows myocardial Jag1- And Jag2- Signalling to Notch1 in this tissue.Timely and spatial perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies.

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Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy

Project description:Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. The developmental origins and mechanistic basis of varying severity of this pathology are unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as a marker upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.

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numb and numblike deleted by Nkx2.5Cre

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