Skin fibroblasts of patients with geleophysic dysplasia due to FBN1 mutations have lysosomal inclusions and losartan improves their microfibril deposition defect.
Adolescent
Bone Diseases, Developmental
/ genetics
Child
Child, Preschool
Extracellular Matrix
Female
Fibrillin-1
/ genetics
Fibroblasts
/ metabolism
Humans
Infant
Limb Deformities, Congenital
/ genetics
Losartan
/ pharmacology
Lysosomes
/ metabolism
Male
Microfibrils
/ metabolism
Signal Transduction
/ drug effects
Skin
/ metabolism
Transforming Growth Factor beta
/ metabolism
extracellular matrix
geleophysic dysplasia
intracytoplasmic inclusions
losartan
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
06
02
2019
revised:
01
06
2019
accepted:
17
06
2019
pubmed:
28
7
2019
medline:
20
6
2020
entrez:
28
7
2019
Statut:
ppublish
Résumé
Geleophysic dysplasia (GPHYSD) is a disorder characterized by dysmorphic features, stiff joints and cardiac involvement due to defects of TGF-β signaling. GPHYSD can be caused by mutations in FBN1, ADAMTLS2, and LTBP3 genes. Consistent with previous reports, we found intracellular inclusions of unknown material by electron microscopy (EM) in skin fibroblasts of two GPHYSD individuals carrying FBN1 mutations. Moreover, we found that the storage material is enclosed within lysosomes and is associated with the upregulation of several lysosomal genes. Treatment of GPHYSD fibroblasts carrying FBN1 mutations with the angiotensin II receptor type 1 inhibitor losartan that inhibits TGF-β signaling did not reduce the storage but improved the extracellular deposition of fibrillin-1 microfibrils. Losartan is a promising candidate drug for treatment of GPHYSD due to FBN1 defects.
Sections du résumé
BACKGROUND
Geleophysic dysplasia (GPHYSD) is a disorder characterized by dysmorphic features, stiff joints and cardiac involvement due to defects of TGF-β signaling. GPHYSD can be caused by mutations in FBN1, ADAMTLS2, and LTBP3 genes.
METHODS AND RESULTS
Consistent with previous reports, we found intracellular inclusions of unknown material by electron microscopy (EM) in skin fibroblasts of two GPHYSD individuals carrying FBN1 mutations. Moreover, we found that the storage material is enclosed within lysosomes and is associated with the upregulation of several lysosomal genes. Treatment of GPHYSD fibroblasts carrying FBN1 mutations with the angiotensin II receptor type 1 inhibitor losartan that inhibits TGF-β signaling did not reduce the storage but improved the extracellular deposition of fibrillin-1 microfibrils.
CONCLUSION
Losartan is a promising candidate drug for treatment of GPHYSD due to FBN1 defects.
Identifiants
pubmed: 31350823
doi: 10.1002/mgg3.844
pmc: PMC6732269
doi:
Substances chimiques
FBN1 protein, human
0
Fibrillin-1
0
Transforming Growth Factor beta
0
Losartan
JMS50MPO89
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e844Informations de copyright
© 2019 Telethon Foundation. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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