title: GALNT3, a gene associated with hyperphosphatemic familial tumoral calcinosis, is transcriptionally regulated by extracellular phosphate and modulates matrix metalloproteinase activity.
abstract: GALNT3 encodes UDP-N-acetyl-alpha-d-galactosamine: polypeptide N-acetylgalactosaminyl-transferarase 3 (ppGalNacT3), a glycosyltransferase which has been suggested to prevent proteolysis of FGF23, a potent phosphaturic protein. Accordingly, loss-of-function mutations in GALNT3 cause hyperphosphatemic familial tumoral calcinosis (HFTC), a rare autosomal recessive disorder manifesting with increased kidney reabsorption of phosphate, resulting in severe hyperphosphatemia and widespread ectopic calcifications. Although these findings definitely attribute a role to ppGalNacT3 in the regulation of phosphate homeostasis, little is currently known about the factors regulating GALNT3 expression. In addition, the effect of decreased GALNT3 expression in peripheral tissues has not been explored so far. In the present study, we demonstrate that GALNT3 expression is under the regulation of a number of factors known to be associated with phosphate homeostasis, including inorganic phosphate itself, calcium and 1,25-dihydroxyvitamin D(3). In addition, we show that decreased GALNT3 expression in human skin fibroblasts leads to increased expression of FGF7 and of matrix metalloproteinases, which have been previously implicated in the pathogenesis of ectopic calcification. Thus, the present data suggest that ppGalNacT3 may play a role in peripheral tissues of potential relevance to the pathogenesis of disorders of phosphate metabolism.
authors.affiliation: Laboratory of Molecular Dermatology and Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Chefetz
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
mesh_terms: D001483:Base Sequence; D002114:Calcinosis / Q000201:enzymology* / Q000235:genetics*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D045604:Extracellular Fluid / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D054559:Hyperphosphatemia / Q000201:enzymology* / Q000235:genetics*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D010710:Phosphates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000201:enzymology / Q000378:metabolism; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D017931:DNA Primers; D051523:Fibroblast Growth Factor 7; D000089703:Fibroblast Growth Factor-23; D020782:Matrix Metalloproteinases; D017350:N-Acetylgalactosaminyltransferases; D010710:Phosphates; D034741:RNA, Small Interfering; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human; C496453:FGF7 protein, human