Abstract
ABSTRACTThe ADAMTS family comprises 19 secreted metalloproteinases that cleave extracellular matrix components and have diverse functions in numerous disease and physiological contexts. A number of them remain ‘orphan’ proteases and among them is ADAMTS18, which has been implicated in developmental eye disorders, platelet function and various malignancies. To assess in vivo function of ADAMTS18, we generated a mouse strain with inactivated Adamts18 alleles. In the C57Bl6/Ola background, Adamts18-deficient mice are born in a normal Mendelian ratio, and are viable but show a transient growth delay. Histological examination revealed a 100% penetrant eye defect resulting from leakage of lens material through the lens capsule occurring at embryonic day (E)13.5, when the lens grows rapidly. Adamts18-deficient lungs showed altered bronchiolar branching. Fifty percent of mutant females are infertile because of vaginal obstruction due to either a dorsoventral vaginal septum or imperforate vagina. The incidence of ovarian rete is increased in the mutant mouse strain. Thus, Adamts18 is essential in the development of distinct tissues and the new mouse strain is likely to be useful for investigating ADAMTS18 function in human disease, particularly in the contexts of infertility and carcinogenesis.
Highlights
ADAMTS18 is a member of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin type 1 Motifs (ADAMTS) family of secreted Zn-dependent metalloproteinases (Kuno et al, 1997) that comprises 19 members as reviewed in (Apte, 2009, Kelwick et al, 2015)
In the C57Bl6/Ola background, Adamts18 deficient mice are born in a normal Mendelian ratio, and are viable but show a transient growth delay
Adamts18 is essential in the development of distinct tissues and the new mouse strain is likely to be useful for investigating ADAMTS18 function in human disease, in the contexts of infertility and carcinogenesis
Summary
ADAMTS18 is a member of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin type 1 Motifs (ADAMTS) family of secreted Zn-dependent metalloproteinases (Kuno et al, 1997) that comprises 19 members as reviewed in (Apte, 2009, Kelwick et al, 2015). The catalytic activity of ADAMTS proteases depends on zinc ion binding in the active site; unique to ADAMTS proteinases is a characteristically organized ancillary domain containing thrombospondin type 1 repeats (TSRs) (Shieh et al, 2008). Germ line mutations in ADAMTS genes have been implicated in a number of human genetic disorders (Dubail and Apte, 2015). A homozygous missense mutation in one of the C-terminal thrombospondin repeats of ADAMTS18 was detected in a patient suffering from early-onset severe retinal dystrophy and implicated in photoreceptor function (Peluso et al, 2013a)
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