title: SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.
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.
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Piccolo
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Mithbaokar
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Sabatino
authors.affiliation: Ferguson-Smith Department of Clinical Genetics, Yorkhill Hospital, Glasgow, UK.
authors.forename: John
authors.initials: J
authors.lastname: Tolmie
authors.affiliation: Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Melis
authors.affiliation: Clinica Pediatrica, Istituto G. Gaslini, Genova, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Schiaffino
authors.affiliation: Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, Istituto G. Gaslini, Genova, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.affiliation: Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.affiliation: 1] Telethon Institute of Genetics and Medicine, Naples, Italy [2] Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003456:Cryptorchidism / Q000235:genetics* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D019066:Facies; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism*; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy / Q000235:genetics* / Q000378:metabolism*; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism*; D007592:Joint Diseases / Q000235:genetics* / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000378:metabolism; D020894:Microfibrils / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult
chemical_list: D051899:Smad2 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D008666:Metalloendopeptidases; D019808:Losartan