Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics

The mammalian ADAMTS superfamily comprises 19 secreted metalloproteinases and 7 ADAMTS-like proteins, each the product of a distinct gene. Thus far, all appear to be relevant to extracellular matrix function or to cell-matrix interactions. Most ADAMTS functions first emerged from analysis of spontaneous human and animal mutations and genetically engineered animals. The clinical manifestations of Mendelian disorders resulting from mutations in ADAMTS2, ADAMTS10, ADAMTS13, ADAMTS17, ADAMTSL2 and ADAMTSL4 identified essential roles for each gene, but also suggested potential cooperative functions of ADAMTS proteins. These observations were extended by analysis of spontaneous animal mutations, such as in bovine ADAMTS2, canine ADAMTS10, ADAMTS17 and ADAMTSL2 and mouse ADAMTS20. These human and animal disorders are recessive and their manifestations appear to result from a loss-of-function mechanism. Genome-wide analyses have determined an association of some ADAMTS loci such as ADAMTS9 and ADAMTS7, with specific traits and acquired disorders. Analysis of genetically engineered rodent mutations, now achieved for over half the superfamily, has provided novel biological insights and animal models for the respective human genetic disorders and suggested potential candidate genes for related human phenotypes. Engineered mouse mutants have been interbred to generate combinatorial mutants, uncovering cooperative functions of ADAMTS proteins in morphogenesis. Specific genetic models have provided crucial insights on mechanisms of osteoarthritis (OA), a common adult-onset degenerative condition. Engineered mutants will facilitate interpretation of exome variants identified in isolated birth defects and rare genetic conditions, as well as in genome-wide screens for trait and disease associations. Mammalian forward and reverse genetics, together with genome-wide analysis, together constitute a powerful force for revealing the functions of ADAMTS proteins in physiological pathways and health disorders. Their continuing use, together with genome-editing technology and the ability to generate stem cells from mutants, presents numerous opportunities for advancing basic knowledge, human disease pathways and therapy.