Skin fibroblasts of patients with geleophysic dysplasia due to FBN1 mutations have lysosomal inclusions and losartan improves their microfibril deposition defect
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Medientyp:
E-Artikel
Titel:
Skin fibroblasts of patients with geleophysic dysplasia due to FBN1 mutations have lysosomal inclusions and losartan improves their microfibril deposition defect
Erschienen in:Molecular Genetics & Genomic Medicine
Sprache:
Englisch
DOI:
10.1002/mgg3.844
ISSN:
2324-9269
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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 <jats:italic>FBN1</jats:italic>, <jats:italic>ADAMTLS2</jats:italic>, and <jats:italic>LTBP3</jats:italic> genes.</jats:p></jats:sec><jats:sec><jats:title>Methods and Results</jats:title><jats:p>Consistent with previous reports, we found intracellular inclusions of unknown material by electron microscopy (EM) in skin fibroblasts of two GPHYSD individuals carrying <jats:italic>FBN1</jats:italic> 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 <jats:italic>FBN1</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Losartan is a promising candidate drug for treatment of GPHYSD due to <jats:italic>FBN1</jats:italic> defects.</jats:p></jats:sec>