ADAMTS and ADAMTSL mutations in connective tissue disorders

The ADAMTS family are extracellular matrix (ECM) proteins and enzymes involved in regulating tissue structure and function. The ECM is a network of proteins and polysaccharides surrounding the cells that provide support and maintain cellular function. Mutations to proteins in the ECM lead to systemic connective tissue disorders by disrupting the structural integrity and maintenance of the ECM, resulting in ocular, musculoskeletal, skin, and cardiovascular abnormalities. Mutations that arise from the ADAMTS family lead to specific connective tissue disorders with distinct clinical characteristics. Here, we detail these distinct clinical features of major connective tissue disorders that arise from mutations in the ADAMTS family proteins. These include Ehlers Danlos syndrome arising from mutation in ADAMTS2, Geleophysic Dysplasia from ADAMTSL2, Weill-Marchesani Syndrome from ADAMTS10 and ADAMTS17, Ectopia lentis from ADAMTSL4, thoracic aortic aneurysms and dissection from ADAMTSL6, valvular disease in ADAMTS19, and a further connective tissue disorder from mutations in ADAMTS6. This review details the mechanisms in which mutations to these ADAMTS genes impair the structure of the ECM, leading to the variety of phenotypic outcomes seen in connective tissue disorders.