ADAMTS proteins as modulators of microfibril formation and function

By D. Hubmacher, S. Apte. 2015

152 citations recorded by the source corpus.

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.

Subfields: Genetics, Immunology and Allergy, Rheumatology

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In Genetics

1. S. Apte
2. S. Zhong
3. R. Khalil
4. T. Mead

In Immunology and Allergy

1. S. Zhong
2. R. Khalil
3. T. Mead
4. S. Apte

In Rheumatology

1. R. Khalil

Citations in the corpus

• A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “Mutations in ADAMTS-10 and 17 have been associated with Weill–Marchesani syndrome, characterized by short stature, acromelic dysplasia and disproportionate distal limb shortening [43, 108, 109].”
• ADAMTS proteins in human disorders (2018, background): “ADAMTSL4 and ADAMTSL6 comprise a homologous pair in which TSR1 is split by an insertion.”