title: Two novel GALNT3 mutations in familial tumoral calcinosis.
abstract: Familial tumoral calcinosis (TC) is characterized by elevated serum phosphate concentrations, normal or elevated 1,25(OH)2 vitamin D, as well as periarticular and vascular calcifications. Recessive mutations in the mucin-like glycosyltransferase GalNAc transferase-3 (GALNT3) and the phosphaturic hormone fibroblast growth factor-23 (FGF23) have been shown to result in TC. In the present study, mutational analyses were performed on two patients with TC to determine the molecular basis of their diseases. Analysis of the first patient revealed a novel, homozygous base insertion (1102_1103insT) in GALNT3 exon 5 that results in a frameshift and premature stop codon (E375X). The second patient had a novel homozygous transition (1460 g>a) in GALNT3 exon 7, which caused a nonsense mutation (W487X). Both mutations are predicted to markedly truncate the mature GALNT3 protein product. Although the patients carry GALNT3 mutations, these individuals presented with low-normal serum concentrations of intact biologically active FGF23 and high levels of C-terminal FGF23. In order to discern a possible relationship between GALNT3 and FGF23 in TC, a comprehensive assessment of the reported TC mutations was also performed. In summary, we have detected novel GALNT3 mutations that result in familial TC, and show that disturbed serum FGF23 concentrations are present in our TC cases as well as in previously reported cases. These studies expand our current genetic understanding of familial TC, and support a pathophysiological association between GALNT3 and FGF23.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, and Department of Orthopedics, Imam Khomeini University Hospital, Tehran, Iran.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Garringer
authors.forename: Seyed Mohammad Javad
authors.initials: SM
authors.lastname: Mortazavi
authors.forename: Fatemehsadat
authors.initials: F
authors.lastname: Esteghamat
authors.forename: Mahdi
authors.initials: M
authors.lastname: Malekpour
authors.forename: Harika
authors.initials: H
authors.lastname: Boztepe
authors.forename: Refik
authors.initials: R
authors.lastname: Tanakol
authors.forename: Siobhan I
authors.initials: SI
authors.lastname: Davis
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: White
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002114:Calcinosis / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human