title: A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome.
abstract: OBJECTIVE
  Hyperostosis-hyperphosphataemia syndrome (HHS) is a rare hereditary disorder characterized by hyperphosphataemia, inappropriately normal or elevated 1,25-dihydroxyvitamin D(3) and localized painful cortical hyperostosis. HHS was shown to be caused by inactivating mutations in GALNT3, encoding UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3). Herein, we sought to identify the genetic cause of hyperphosphataemia and tibial hyperostosis in a 19-year-old girl of Colombian origin.
  
  
  METHODS
  Genomic DNA was extracted and sequencing analysis of the GALNT3 and fibroblast growth factor 23 (FGF23) genes performed. Serum levels of intact and C-terminal FGF23 were measured using two different ELISA methods.
  
  
  RESULTS
  Mutational analysis identified a novel homozygous missense mutation in exon 6 of GALNT3 (1584 G>A), leading to an amino acid shift from Arg to His at residue 438 (R438H). The mutation was not found in over 200 control alleles or in any single nucleotide polymorphism databases. The R438 residue is highly conserved throughout species and in all known GalNAc-transferase family members. Modelling predicted the substitution deleterious for protein structure. Importantly, the phosphaturic factor FGF23 was differentially processed, as reflected by low intact (15 pg/ml) but high C-terminal (839 RU/ml) serum FGF23 levels.
  
  
  CONCLUSIONS
  We report on the first missense mutation in GALNT3 giving rise to HHS, since previous GALNT3 mutations in HHS caused aberrant splicing or premature truncation of the protein. The R438H substitution likely abrogates GALNT3 activity, in turn causing enhanced FGF23 degradation and subsequent hyperostosis/hyperphosphataemia.
authors.affiliation: Department of Medical Sciences, Uppsala University Hospital, Ing.70, 3 tr, 75185 Uppsala, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.forename: Tijana
authors.initials: T
authors.lastname: Krajisnik
authors.forename: Charlotta
authors.initials: C
authors.lastname: Larsson
authors.forename: Bengt
authors.initials: B
authors.lastname: Lindberg
authors.forename: Tobias E
authors.initials: TE
authors.lastname: Larsson
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics; D006801:Humans; D015576:Hyperostosis / Q000235:genetics* / Q000473:pathology; D054559:Hyperphosphatemia / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; 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