Dataset Information

SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

ABSTRACT: Myhre syndrome (MS, MIM 139210) is a connective tissue disorder that presents with short stature, short hands and feet, facial dysmorphic features, muscle hypertrophy, thickened skin, and deafness. Recurrent missense mutations in SMAD4 encoding for a transducer mediating transforming growth factor β (TGF-β) signaling are responsible for MS. We found that MS fibroblasts showed increased SMAD4 protein levels, impaired matrix deposition, and altered expression of genes encoding matrix metalloproteinases and related inhibitors. Increased TGF-β signaling and progression of aortic root dilation in Marfan syndrome can be prevented by the antihypertensive drug losartan, a TGF-β antagonists and angiotensin-II type 1 receptor blocker. Herein, we showed that losartan normalizes metalloproteinase and related inhibitor transcript levels and corrects the extracellular matrix deposition defect in fibroblasts from MS patients. The results of this study may pave the way toward therapeutic applications of losartan in MS.

SUBMITTER: Piccolo P

PROVIDER: S-EPMC3984901 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

Piccolo Pasquale P Mithbaokar Pratibha P Sabatino Valeria V Tolmie John J Melis Daniela D Schiaffino Maria Cristina MC Filocamo Mirella M Andria Generoso G Brunetti-Pierri Nicola N

European journal of human genetics : EJHG 20140108 8

Myhre syndrome (MS, MIM 139210) is a connective tissue disorder that presents with short stature, short hands and feet, facial dysmorphic features, muscle hypertrophy, thickened skin, and deafness. Recurrent missense mutations in SMAD4 encoding for a transducer mediating transforming growth factor β (TGF-β) signaling are responsible for MS. We found that MS fibroblasts showed increased SMAD4 protein levels, impaired matrix deposition, and altered expression of genes encoding matrix metalloprotei ...[more]

PMID: 24398790

Similar Datasets

Project description:BACKGROUND: A better understanding of the molecular mechanism of aortic valve development and bicuspid aortic valve (BAV) formation would significantly improve and optimize the therapeutic strategy for treating BAV patients. Over the past decade, the genes involved in aortic valve development and BAV formation has been increasingly recognized. On the other hand, ADAMTS gene family members have been reported to be able to modulate cardiovascular development and diseases. The present study aimed to further investigate the roles of ADAMTS family members in aortic valve development and BAV formation. METHODS: Morpholino-based ADAMTS family gene-targeted screening for zebrafish heart outflow tract phenotypes combined with DNA sequencing in a 304 cohort BAV patient registry study was initially carried out to identify potentially related genes. Both ADAMTS gene-specific fluorescence in situ hybridization assay and genetic tracing experiments were then performed to evaluate the expression pattern in the aortic valve Accordingly, related genetic mouse models (both knock-out and knock-in) were generated using the CRISPR/Cas9 method to further study the roles of ADAMTS family genes. The lineage tracing technique was used again to evaluate how the cellular activity of specific progenitor cells was regulated by ADAMTS genes. Bulk RNA sequencing was used to investigate the signaling pathways involved. Both inducible pluripotent stem cells (iPSC) derived from BAV patients and genetic mouse tissue were used to study the molecular mechanism of the gene. Immunohistochemistry using different antibodies was performed to describe the phenotype of cardiac valve anomalies, especially in the ECM components. RESULTS: ADAMTS genes targeted phenotype screening in zebrafish and targeted DNA sequencing on a cohort of BAV patients identified ADAMTS16 as a BAV-causing gene and found the ADAMTS16 p.H357Q variant in an inherited BAV family. In addition, both in situ hybridization and genetic tracing studies described a unique spatiotemporal pattern of ADAMTS16 expression during aortic valve development. Adamts16+/- and Adamts16+/H355Q mouse models both exhibited an R-NC-type BAV phenotype, with progressive aortic valve thickening associated with raphe formation (fusion of the commissure). Conditional Adamts16 mutant mouse models further demonstrated that Adamts16 deficiency mainly in endothelial lineage cells recapitulated the BAV phenotype. This was confirmed in lineage tracing mouse models in which Adamts16 deficiency affected endothelial and second heart field cells, not the neural crest cells. Accordingly, the changes were mainly detected in the noncoronary and right coronary leaflets. Bulk RNA sequencing using iPSC-induced endothelial cells (iPSC-ECs) and genetic mouse embryonic heart tissue unveiled enhanced FAK signaling, which was accompanied by elevated fibronectin levels. Both in vitro iPSC-ECs culture and ex vivo embryonic outflow tract explant studies validated the altered FAK signaling. CONCLUSIONS: Our present study identified a novel BAV-causing ADAMTS16 p. H357Q variant. ADAMTS16 deficiency led to BAV formation. We then performed gene expression profiling analysis using data obtained from RNA-seq of 15 different tissues of different genetic mice.

Dataset Information

SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

Publications

SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets