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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.

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Figure 1: Mib1 inactivation in the myocardium causes LVNC.
Figure 2: Mutations in human MIB1 cause LVNC.
Figure 3: Patients with LVNC with MIB1 mutations have reduced expression of N1ICD, DTX1 and GATA3.
Figure 4: MIB1 is a homodimer whose ubiquitin ligase activity is impaired by the identified mutations.
Figure 5: Defective ventricular maturation and cardiac gene expression in Mib1flox; cTnT-cre mice.
Figure 6: Proposed mechanism of Notch pathway function in trabecular maturation and compaction.

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Acknowledgements

We thank P.J. Gallagher (Indiana University) for the Mib1-specific antibody, U. Lendahl (Karolinska Institute) for the Jag1- and Notch1-HEK293 cells, A. Martín-Pendas (Cancer Center, CSIC, Salamanca) for the pCELF plamid, D. Saura and J. González for carrying out the CMRI of the patients, M. Manzanares, A. Martín-Pendas, J.M. Pérez-Pomares, J.M. Redondo, J.J. Schott and M. Torres for critical reading of the manuscript and S. Bartlett (CNIC) for English editing. This study was funded by grants SAF2010-17555, RD06/0014/0038 (RECAVA) and RD06/0010/1013 (TERCEL) from the Spanish Ministry of Economy and Competition (MINECO) to J.L.d.l.P. G.L. has a PhD fellowship from the MINECO (FPI Program, BES-2008-002904). The CNIC is supported by the MINECO and the Pro-CNIC Foundation.

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Contributions

G.L., J.C.C., B.M.-P., D.M., A.G.-R., B.P., G.D. and D.D. performed experiments. C.T. analyzed the sequencing data, F.M. performed in silico modeling, J.L.I.-G. performed CMRI in mice, and Y.-Y.K. provided the Mib1 conditional mutant. G.P., M.S.-M., B.I., C.M., P.G.-P., J.R.G. and L.M. provided samples, and diagnosed and evaluated patients with LVNC. L.F.-F. and L.J.J.-B. performed and evaluated echocardiography in mice and performed CMRI on the parents of the probands. J.L.d.l.P. designed experiments, reviewed the data and wrote the manuscript. All authors reviewed the manuscript during its preparation.

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Correspondence to José Luis de la Pompa.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Tables 1 and 2 (PDF 1730 kb)

Supplementary Video 1

6-month-old wild-type (WT) echocardiography analysis. Ep, epicardium; en, endocardium. (AVI 740 kb)

Supplementary Video 2

6-month-old Mib1flox;cTnT-Cre echocardiography analysis. Ep, epicardium. Asterisks mark where prominent trabeculae can be observed. (AVI 755 kb)

Supplementary Video 3

6-month-old WT CMRI. 4 chambers view. (AVI 199 kb)

Supplementary Video 4

6-month-old WT CMRI. short axis view. (AVI 176 kb)

Supplementary Video 5

6-month-old Mib1flox;cTnT-Cre CMRI 4 chambers view. (AVI 220 kb)

Supplementary Video 6

6-month-old Mib1flox;cTnT-Cre CMRI short axis view. (AVI 66 kb)

Supplementary Video 7

Healthy control CMRI 4 chamber view (AVI 630 kb)

Supplementary Video 8

Patient 1.II.3 CMRI 4 chamber view. (AVI 542 kb)

Supplementary Video 9

Patient 2.I.2 CMRI 4 chamber view. (AVI 735 kb)

Supplementary Video 10

Healthy control CMRI 2 chamber view. (AVI 555 kb)

Supplementary Video 11

Patient 1.II.3 CMRI 2 chamber view. (AVI 611 kb)

Supplementary Video 12

Patient 2.I.2 CMRI 2 chamber view. (AVI 388 kb)

Supplementary Video 13

Healthy control CMRI short axis view. (AVI 370 kb)

Supplementary Video 14

Patient 1.II.3 CMRI short axis view. (AVI 448 kb)

Supplementary Video 15

Patient 2.I.2 CMRI short axis view. (AVI 499 kb)

Supplementary Table 3

Ventricular alterations and non-compaction index in LVNC affected family members and control individuals based on echocardiographic and CMRI data. (XLS 39 kb)

Supplementary Data Set 1

E14.5 WT vs. Mib1flox;cTnT-Cre. RNA-Seq data, all genes (XLSX 140 kb)

Supplementary Data Set 2

E14.5 WT vs. Mib1flox;cTnT-Cre. RNA-Seq data, only up-regulated and down-regulated genes (XLSX 2123 kb)

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Luxán, G., Casanova, J., Martínez-Poveda, B. et al. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat Med 19, 193–201 (2013). https://doi.org/10.1038/nm.3046

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