uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. (Metabola bensjukdomar, Fosfatmetabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. (Metabola bensjukdomar, Fosfatmetabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. (Metabola bensjukdomar, Fosfatmetabolism)
Malmö University Hospital, Dept. of Medicine.
Show others and affiliations
2008 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 158, no 6, 929-934 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Hyperostosis–hyperphosphataemia syndrome (HHS) is a rare hereditary disorder characterized by hyperphosphataemia, 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-a-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 GOA), 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.

Place, publisher, year, edition, pages
Bristol: BioScientifica Ltd , 2008. Vol. 158, no 6, 929-934 p.
Keyword [en]
GALNT3, GalNac-T3, FGF23, FGF-23, fibroblast growth factor-23, fibroblast growth factor 23, hyperostosis-hyperphosphatemia syndrome, hyperostosis-hyperphosphataemia syndrome, HHS, phosphate, mutation
National Category
Endocrinology and Diabetes
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-107376DOI: 10.1530/EJE-08-0011ISI: 000256812800019OAI: oai:DiVA.org:uu-107376DiVA: diva2:228956
Available from: 2009-08-12 Created: 2009-08-10 Last updated: 2011-04-11Bibliographically approved
In thesis
1. Fibroblast growth factor-23 and Klotho in bone/mineral and parathyroid disorders
Open this publication in new window or tab >>Fibroblast growth factor-23 and Klotho in bone/mineral and parathyroid disorders
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fibroblast growth factor-23 (FGF23) is a novel, bone-produced hormone that regulates renal phosphate (Pi) reabsorption and calcitriol metabolism. Disorders of mineral and bone metabolism, such as autosomal dominant hypophosphatemic rickets (ADHR) and hyperostosis-hyperphosphatemia syndrome (HHS), witness the importance of well-balanced serum levels of FGF23. Patients with chronic kidney disease (CKD) are highly morbid due to Pi retention/hyperphosphatemia and calcitriol deficiency, which lead to elevated serum levels of parathyroid hormone (PTH) and secondary hyperparathyroidism (sHPT). As a response to hyperphosphatemia, CKD patients have also remarkably high serum FGF23 levels, which are associated with cardiovascular risk factors and increased mortality in CKD. The overall aim of this dissertation was to discern a possible role of FGF23 in parathyroid biology. Our in vitro experiments on isolated bovine parathyroid cells demonstrate that FGF23 directly and dose-dependently suppresses the PTH production and secretion, while increasing the expression of the 25-hydroxyvitamin D3-activating enzyme 1α-hydroxylase. We investigated possible expressional changes in the FGF23 receptor co-factor Klotho in hyperparathyroid disorders and found that Klotho expression is decreased or absent and inversely correlated to serum calcium (Ca) in adenomas of primary HPT (pHPT). In the hyperplastic parathyroid glands of sHPT, Klotho expression declines in parallel with the kidney function and correlates with the glomerular filtration rate. Moreover, Klotho expression is suppressed by Ca and FGF23, increased by calcitriol, but unaffected by Pi and PTH in vitro. Finally, we identified a novel missense mutation in the gene encoding GALNT3, which is normally involved in the post-translational glycosylation of FGF23, as the cause of aberrant FGF23 processing in a patient with HHS. In summary, we provide evidence for a novel bone/parathyroid axis in which FGF23 functions as a direct, negative regulator of the PTH production. High extracellular Ca is a major determinant of the Klotho expression in pHPT, whereas the Klotho levels in sHPT may be attributed to a combination of the high FGF23 and Ca, and low calcitriol levels associated with CKD. Hence, the decreased Klotho expression in sHPT could explain the concomitantly high FGF23 and PTH levels, as well as the failure of FGF23 to prevent or mitigate the development of sHPT in CKD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 475
Keyword
calcitriol, chronic kidney disease, CKD, chronic renal failure, fibroblast growth factor 23, fibroblast growth factor-23, FGF23, FGF-23, GalNac-T3, GALNT3, GFR, hyperostosis-hyperphosphatemia syndrome, HHS, Klotho, parathyroid hormone, PTH, hyperparathyroidism, pHPT, sHPT, uremic, vitamin D3
National Category
Endocrinology and Diabetes
Research subject
Internal Medicine
Identifiers
urn:nbn:se:uu:diva-107456 (URN)978-91-554-7590-1 (ISBN)
Public defence
2009-09-26, Hörsalen, D1, Klinisk mikrobiologi, Dag Hammarskjölds väg 17, Uppsala, 09:30 (Swedish)
Opponent
Supervisors
Available from: 2009-09-03 Created: 2009-08-12 Last updated: 2009-10-02Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text
By organisation
Internal Medicine
In the same journal
European Journal of Endocrinology
Endocrinology and Diabetes

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 503 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf