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A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome

Olauson, Hannes; Krajisnik, Tijana; Larsson, Charlotta; Lindberg, Bengt LU and Larsson, Tobias E (2008) In European Journal of Endocrinology 158(6). p.929-934
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 hyperphosphataernia 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... (More)
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 hyperphosphataernia 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Journal of Endocrinology
volume
158
issue
6
pages
929 - 934
publisher
Society of the European Journal of Endocrinology
external identifiers
  • wos:000256812800019
  • scopus:44949200184
ISSN
1479-683X
DOI
10.1530/EJE-08-0011
language
English
LU publication?
yes
id
caba8856-6db4-42fa-8853-8910bb4853b2 (old id 1191064)
date added to LUP
2008-09-08 11:11:01
date last changed
2017-09-03 03:38:05
@article{caba8856-6db4-42fa-8853-8910bb4853b2,
  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 hyperphosphataernia 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.},
  author       = {Olauson, Hannes and Krajisnik, Tijana and Larsson, Charlotta and Lindberg, Bengt and Larsson, Tobias E},
  issn         = {1479-683X},
  language     = {eng},
  number       = {6},
  pages        = {929--934},
  publisher    = {Society of the European Journal of Endocrinology},
  series       = {European Journal of Endocrinology},
  title        = {A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome},
  url          = {http://dx.doi.org/10.1530/EJE-08-0011},
  volume       = {158},
  year         = {2008},
}