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

Pasquale Piccolo, Pratibha Mithbaokar, Valeria Sabatino, John Tolmie, Daniela Melis, Maria Cristina Schiaffino, Mirella Filocamo, Generoso Andria, Nicola Brunetti-Pierri

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)988-994
Number of pages7
JournalEuropean Journal of Human Genetics
Volume22
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

Losartan
Transforming Growth Factors
Extracellular Matrix
Mutation
Fibroblasts
Angiotensin II Type 1 Receptor Blockers
Marfan Syndrome
Matrix Metalloproteinase Inhibitors
Metalloproteases
Deafness
Missense Mutation
Transducers
Connective Tissue
Hypertrophy
Antihypertensive Agents
Foot
Dilatation
Hand
Gene Expression
Muscles

Keywords

  • losartan
  • myhre syndrome
  • SMAD4

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan. / Piccolo, Pasquale; Mithbaokar, Pratibha; Sabatino, Valeria; Tolmie, John; Melis, Daniela; Schiaffino, Maria Cristina; Filocamo, Mirella; Andria, Generoso; Brunetti-Pierri, Nicola.

In: European Journal of Human Genetics, Vol. 22, No. 8, 2014, p. 988-994.

Research output: Contribution to journalArticle

Piccolo, Pasquale ; Mithbaokar, Pratibha ; Sabatino, Valeria ; Tolmie, John ; Melis, Daniela ; Schiaffino, Maria Cristina ; Filocamo, Mirella ; Andria, Generoso ; Brunetti-Pierri, Nicola. / SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan. In: European Journal of Human Genetics. 2014 ; Vol. 22, No. 8. pp. 988-994.
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