NCBI Summary:
This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature protein, which may inhibit chondrosarcoma cell proliferation and migration. This gene may regulate blood pressure. [provided by RefSeq, May 2016]
General function
Enzyme, Peptidase/Protease
Comment
Cellular localization
Secreted
Comment
Ovarian function
Comment
Expression regulated by
FSH, WT1
Comment
Transcriptional regulation by the Wilms tumor protein, Wt1, suggests a role of the metalloproteinase Adamts16 in murine genitourinary development. Jacobi CL et al. ADAMTS16 (a disintegrin and metalloproteinase with thrombospondin motifs) is a secreted mammalian metalloproteinase with unknown function. We report here that murine Adamts16 is co-expressed with the Wilms tumor protein, Wt1, in the developing glomeruli of embryonic kidneys. Adamts16 mRNA levels were significantly reduced upon transfection of embryonic murine kidney explants with Wt1 antisense vivo-morpholino. Antisense knockdown of Adamts16 inhibited branching morphogenesis in kidney organ cultures. Adamts16 was detected by in situ mRNA hybridization and/ or immuno-histochemistry also in embryonic gonads, and in spermatids and granulosa cells of adult testes and ovaries, respectively. Silencing of Wt1 by transfection with antisense vivo-morpholino significantly increased Adamts16 mRNA in cultured embryonic XY gonads (11.5 and 12.5 d.p.c.), and reduced Adamts16 transcripts in XX gonads (12.5 and 13.5 d.p.c.). Three predicted Wt1 consensus motifs could be identified in the promoter and the 5-untranslated region of the murine Adamts16 gene. Binding of Wt1 protein to these elements was verified by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). A firefly luciferase reporter gene under control of the Adamts16 promoter was activated approximately 8-fold by transient co-transfection of human granulosa cells with a Wt1 expression construct. Gradual shortening of the 5-flanking sequence successively reduced and eventually abrogated Adamts16 promoter activation by Wt1. These findings demonstrate that Wt1 differentially regulates the Adamts16 gene in XX and XY embryonic gonads. It is suggested that Adamts16 acts immediately downstream of Wt1 during murine urogenital development. We propose that Adamts16 is involved in branching morphogenesis of the kidneys in mice.
Ovarian localization
Granulosa
Comment
FSH stimulates the expression of the ADAMTS-16 protease in mature human ovarian follicles. Gao S et al. We report the characterization of full-length human ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-16, a novel member of the disintegrin and metalloproteinase with thrombospondin motifs (hence ADAMTS) family. ADAMTS-16 is highly expressed both in the kidney and in the ovary, where it is predominantly expressed in the parietal granulosa cells of pre-ovulatory follicles but only slightly expressed in cells of the cumulus oophorus. In fully differentiated luteinizing granulosa cells, follicle-stimulating hormone and forskolin induces expression of ADAMTS-16, suggesting that it is regulated via the cAMP pathway. Luteinizing hormone had a minor effect on the expression of ADAMTS-16. ADAMTS-16 is capable of cleaving alpha(2)-macroglobulin (MG), a common substrate for proteases, which is present at high concentrations in the follicular fluid of ovarian follicles. These studies provide the first evidence that ADAMTS-16 is an active protease and suggest a physiological role of ADAMTS-16 in ovarian follicles, at least during the pre-ovulatory phase.
Follicle stages
Preovulatory
Comment
Phenotypes
POF (premature ovarian failure)
Mutations
1 mutations
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. Patiño LC et al. (2017) Is it possible to identify new mutations potentially associated with non-syndromic primary ovarian insufficiency (POI) via whole-exome sequencing (WES)? WES is an efficient tool to study genetic causes of POI as we have identified new mutations, some of which lead to protein destablization potentially contributing to the disease etiology. POI is a frequently occurring complex pathology leading to infertility. Mutations in only few candidate genes, mainly identified by Sanger sequencing, have been definitively related to the pathogenesis of the disease. This is a retrospective cohort study performed on 69 women affected by POI. WES and an innovative bioinformatics analysis were used on non-synonymous sequence variants in a subset of 420 selected POI candidate genes. Mutations in BMPR1B and GREM1 were modeled by using fragment molecular orbital analysis. Fifty-five coding variants in 49 genes potentially related to POI were identified in 33 out of 69 patients (48%). These genes participate in key biological processes in the ovary, such as meiosis, follicular development, granulosa cell differentiation/proliferation and ovulation. The presence of at least two mutations in distinct genes in 42% of the patients argued in favor of a polygenic nature of POI. It is possible that regulatory regions, not analyzed in the present study, carry further variants related to POI. WES and the in silico analyses presented here represent an efficient approach for mapping variants associated with POI etiology. Sequence variants presented here represents potential future genetic biomarkers. This study was supported by the Universidad del Rosario and Colciencias (Grants CS/CIGGUR-ABN062-2016 and 672-2014). Colciencias supported Liliana Catherine Patiño´s work (Fellowship: 617, 2013). The authors declare no conflict of interest.//////////////////