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A Novel Missense Mutation In GALNT3 Causing Hyperostosis-Hyperphosphatemia Syndrome

H Olauson, Uppsala, Sweden
T Krajisnik, Uppsala, Sweden
C Larsson, Uppsala, Sweden
B Lindberg, Malmö, Sweden
T Larsson, Medical Sciences, Uppsala University, Uppsala, 75185, Sweden

Correspondence: Tobias Larsson, Email: tobias.larsson{at}medsci.uu.se

Abstract

Objective: Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare hereditary disorder characterized by hyperphosphatemia, inappropriately normal or elevated 1,25-dihydroxyvitamin D3 and localized painful cortical hyperostosis. HHS was shown to be caused by inactivating mutations in GALNT3, encoding UDP-N-acetyl--D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3). Herein, we sought to identify the genetic cause of hyperphosphatemia and tibial hyperostosis in a 19-year-old girl of Colombian origin.

Methods: Genomic DNA was extracted and sequencing analysis of the GALNT3 and FGF23 gene performed. Serum levels of intact and C-terminal FGF23 was 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/hyperphosphatemia.