Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 22, Issue 8, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2013.283
Keywords
myhre syndrome; SMAD4; losartan
Funding
- Patients Affected by Genetic Diseases'
- GDB bank of Telethon Genetic Biobank Network [GTF08022, GTB07001]
- Fondazione Telethon [TCBP37TELC, TCBMT3TELD]
- Italian Ministry of Health [GR-2009-1594913]
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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 beta (TGF-beta) 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-beta signaling and progression of aortic root dilation in Marfan syndrome can be prevented by the antihypertensive drug losartan, a TGF-beta 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.
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