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Eur J Hum Genet. 2014 Aug;22(8):988-94. doi: 10.1038/ejhg.2013.283. Epub 2014 Jan 8.

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

Author information

1
Telethon Institute of Genetics and Medicine, Naples, Italy.
2
Ferguson-Smith Department of Clinical Genetics, Yorkhill Hospital, Glasgow, UK.
3
Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
4
Clinica Pediatrica, Istituto G. Gaslini, Genova, Italy.
5
Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto G. Gaslini, Genova, Italy.
6
1] Telethon Institute of Genetics and Medicine, Naples, Italy [2] Department of Translational Medicine, Federico II University of Naples, Naples, Italy.

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.

PMID:
24398790
PMCID:
PMC3984901
DOI:
10.1038/ejhg.2013.283
[Indexed for MEDLINE]
Free PMC Article
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