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

doi:10.1038/ejhg.2013.283

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.

Authors

Pasquale Piccolo¹, Pratibha Mithbaokar¹, Valeria Sabatino¹, John Tolmie², Daniela Melis³, Maria Cristina Schiaffino⁴, Mirella Filocamo⁵, Generoso Andria³, Nicola Brunetti-Pierri⁶

Affiliations

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.

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

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding