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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Cryptorchidism / genetics*
  • Cryptorchidism / metabolism*
  • Extracellular Matrix / metabolism*
  • Facies
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Growth Disorders / genetics*
  • Growth Disorders / metabolism*
  • Hand Deformities, Congenital / genetics*
  • Hand Deformities, Congenital / metabolism*
  • Humans
  • Hypertrophy / genetics*
  • Hypertrophy / metabolism*
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism*
  • Joint Diseases / genetics*
  • Joint Diseases / metabolism*
  • Losartan / pharmacology*
  • Metalloendopeptidases / metabolism
  • Microfibrils / metabolism
  • Mutation*
  • Phosphorylation
  • Signal Transduction / drug effects
  • Smad2 Protein / metabolism
  • Smad4 Protein / genetics*
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta / metabolism
  • Young Adult

Substances

  • Smad2 Protein
  • Smad4 Protein
  • Transforming Growth Factor beta
  • Metalloendopeptidases
  • Losartan

Supplementary concepts

  • Growth mental deficiency syndrome of Myhre