The ADAMTS (a
disintegrin-like and
metalloproteinase domain with
thrombospondin-type 1 motifs) protein superfamily includes 19 secreted
metalloproteases and 7 secreted ADAMTS-like (ADAMTSL)
glycoproteins. The possibility of functional linkage between
ADAMTS proteins and
fibrillin microfibrils was first revealed by a human genetic consilience, in which mutations in ADAMTS10, ADAMTS17, ADAMTSL2 and ADAMTSL4 were found to phenocopy rare
genetic disorders caused by mutations affecting
fibrillin-1 (FBN1), the major microfibril component in adults. The manifestations of these ADAMTS gene disorders in humans and animals suggested that they participated in the structural and regulatory roles of microfibrils. Whereas two such disorders,
Weill-Marchesani syndrome 1 and
Weill-Marchesani-like syndrome involve
proteases (ADAMTS10 and ADAMTS17, respectively),
geleophysic dysplasia and
isolated ectopia lentis in humans involve ADAMTSL2 and ADAMTSL4, respectively, which are not
proteases. In addition to broadly similar dysmorphology, individuals affected by
Weill-Marchesani syndrome 1,
Weill-Marchesani-like syndrome or
geleophysic dysplasia each show characteristic anomalies suggesting molecule-, tissue-, or context-specific functions for the respective
ADAMTS proteins.
Ectopia lentis occurs in each of these conditions except
geleophysic dysplasia, and is due to a defect in the ciliary zonule, which is predominantly composed of FBN1 microfibrils. Together, this strongly suggests that
ADAMTS proteins are involved either in microfibril assembly, stability, and anchorage, or the formation of function-specific supramolecular networks having microfibrils as their foundation. Here, the genetics and molecular biology of this subset of
ADAMTS proteins is discussed from the perspective of how they might contribute to fully functional or function-specific microfibrils.