Skin fibroblasts of patients with geleophysic dysplasia due to FBN1 mutations have lysosomal inclusions and losartan improves their microfibril deposition defect

Abstract

Abstract 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.

Keywords

• extracellular matrix
• geleophysic dysplasia
• intracytoplasmic inclusions
• losartan