Weill-Marchesani syndrome (WMS) is a rare genetic disorder that affects the musculoskeletal system, the eye, and the cardiovascular system. Individuals with WMS present with short stature, joint contractures, thick skin, microspherophakia, small and dislocated lenses, and cardiac valve anomalies. WMS can be caused by recessive mutations in ADAMTS10 (WMS 1), ADAMTS17 (WMS 4), or LTBP2 (WMS 3), or by dominant mutations in fibrillin-1 (FBN1) (WMS 2); all genes encode secreted extracellular matrix (ECM) proteins. Individuals with WMS 4 due to ADAMTS17 mutations appear to have less severe cardiac involvement and present predominantly with the musculoskeletal and ocular features of WMS. ADAMTS17 is a member of the ADAMTS family of secreted proteases and directly binds to fibrillins. Here we report a novel pathogenic variant in ADAMTS17 that causes WMS 4 in an individual with short stature, brachydactyly, and small, spherical, and dislocated lenses. We provide biochemical and cell biological insights in the pathomechanisms of WMS 4, which also suggest potential biological functions for ADAMTS17. We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts. In accordance, transmission electron microscopy revealed elastic fiber abnormalities, decreased collagen fibril diameters, and intracellular collagen accumulation in the dermis of the proband. Together, the data indicate a possible role for ADAMTS17 in the secretion of fibrillin-1 and collagen type I or in their early assembly in the pericellular matrix or the ECM.

Weill-Marchesani综合征（WMS）是一种罕见的遗传性疾病，会影响肌肉骨骼系统，眼睛和心血管系统。患有WMS的个体表现为身材矮小，关节挛缩，皮肤增厚，微球蛋白，晶状体小而脱位以及心脏瓣膜异常。WMS可能由ADAMTS10（WMS 1），ADAMTS17（WMS 4）或LTBP2（WMS 3）的隐性突变或原纤维蛋白1（FBN1）的显性突变（WMS 2）引起; 所有基因都编码分泌的细胞外基质（ECM）蛋白。由于ADAMTS17而具有WMS 4的个人突变似乎没有那么严重的心脏受累，并且主要表现为WMS的肌肉骨骼和眼部特征。ADAMTS17是分泌型蛋白酶ADAMTS家族的成员，可直接与原纤维蛋白结合。在这里我们报告ADAMTS1中的新型致病性变异7会导致WMS 4出现在身材矮小，近视和小，球形和错位的个体中。我们提供有关WMS 4致病机理的生化和细胞生物学见解，还提出了ADAMTS17的潜在生物学功能。我们显示出ADAMTS17中的变体阻止了其分泌，并且我们在源自患者的皮肤成纤维细胞中发现了fibrillin-1和I型胶原的细胞内蓄积。因此，透射电子显微镜显示弹性纤维异常，胶原原纤维直径减小以及先证者真皮中的细胞内胶原积聚。总之，数据表明ADAMTS17在原纤维蛋白-1和I型胶原的分泌或它们在细胞周围基质或ECM中的早期组装中的可能作用。