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Familial Left Ventricular Non-Compaction Is Associated With a Rare p.V407I Variant in Bone Morphogenetic Protein 10
- Source :
- Circulation journal : official journal of the Japanese Circulation Society. 83(8)
- Publication Year :
- 2019
-
Abstract
- Background Left ventricular non-compaction (LVNC) is a heritable cardiomyopathy characterized by hypertrabeculation, inter-trabecular recesses and thin compact myocardium, but the genetic basis and mechanisms remain unclear. This study identified novel LVNC-associated mutations inNOTCH-dependent genes and investigated their mutational effects.Methods and Results:High-resolution melting screening was performed in 230 individuals with LVNC, followed by whole exome and Sanger sequencing of available family members. Dimerization of bone morphogenetic protein 10 (BMP10) and its binding to BMP receptors (BMPRs) were evaluated. Cellular differentiation, proliferation and tolerance to mechanical stretch were assessed in H9C2 cardiomyoblasts, expressing wild-type (WT) or mutant BMP10 delivered by adenoviral vectors. Rare variants, p.W143*-NRG1and p.V407I-BMP10, were identified in 2 unrelated probands and their affected family members. Although dimerization of mutant V407I-BMP10 was preserved like WT-BMP10, V407I-BMP10 pulled BMPR1a and BMPR2 receptors more weakly compared with WT-BMP10. On comparative gene expression and siRNA analysis, expressed BMPR1a and BMPR2 receptors were responsive to BMP10 treatment in H9C2 cardiomyoblasts. Expression of V407I-BMP10 resulted in a significantly lower rate of proliferation in H9C2 cells compared with WT-BMP10. Cyclic stretch resulted in destruction and death of V407I-BMP10 cells. Conclusions The W143*-NRG1and V470I-BMP10variants are associated with LVNC. Impaired BMPR-binding ability, perturbed proliferation and differentiation processes and intolerance to stretch in V407I-BMP10 mutant cardiomyoblasts may underlie myocardial non-compaction.
- Subjects :
- Male
Cellular differentiation
Mutant
030204 cardiovascular system & hematology
Bone Morphogenetic Protein Receptors, Type II
Mechanotransduction, Cellular
Polymorphism, Single Nucleotide
03 medical and health sciences
Mice
0302 clinical medicine
Gene expression
Medicine
Animals
Humans
Genetic Predisposition to Disease
Myocytes, Cardiac
030212 general & internal medicine
Receptor
Exome
Bone Morphogenetic Protein Receptors, Type I
Cell Proliferation
Isolated Noncompaction of the Ventricular Myocardium
business.industry
Bone morphogenetic protein 10
Cell Differentiation
General Medicine
BMPR1A
BMPR2
Cell biology
Rats
HEK293 Cells
Phenotype
Case-Control Studies
Bone Morphogenetic Proteins
Mutation
Female
Cardiology and Cardiovascular Medicine
business
Protein Binding
Subjects
Details
- ISSN :
- 13474820
- Volume :
- 83
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Circulation journal : official journal of the Japanese Circulation Society
- Accession number :
- edsair.doi.dedup.....60ccb3f12be95442a2176de576941764