因 FBN1 突变导致的弹性假黄瘤病患者的皮肤成纤维细胞存在溶酶体包涵体，氯沙坦可改善其微纤维沉积缺陷。
Skin fibroblasts of patients with geleophysic dysplasia due to FBN1 mutations have lysosomal inclusions and losartan improves their microfibril deposition defect.
机构信息
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
出版信息
Mol Genet Genomic Med. 2019 Sep;7(9):e844. doi: 10.1002/mgg3.844. Epub 2019 Jul 27.
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.
背景
Geleophysic 发育不良（GPHYSD）是一种以畸形特征、关节僵硬和心脏受累为特征的疾病，其原因是 TGF-β 信号通路的缺陷。GPHYSD 可由 FBN1、ADAMTLS2 和 LTBP3 基因突变引起。
方法和结果
通过电镜（EM），我们发现了两名携带 FBN1 突变的 GPHYSD 个体的皮肤成纤维细胞中存在未知物质的细胞内包涵体。此外，我们发现储存物质被包含在溶酶体中，并与几个溶酶体基因的上调有关。用血管紧张素 II 受体 1 抑制剂氯沙坦（losartan）治疗携带 FBN1 突变的 GPHYSD 成纤维细胞，该药物可抑制 TGF-β 信号通路，但不能减少储存，反而改善了纤维连接蛋白 1 微纤维的细胞外沉积。
结论
由于 FBN1 缺陷，氯沙坦是治疗 GPHYSD 的一种很有前途的候选药物。
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