Journal of Molecular Medicine

, Volume 83, Issue 1, pp 33–38

Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders

Authors

  • Yaacov Frishberg
    • Division of Pediatric NephrologyShaare Zedek Medical Center
  • Orit Topaz
    • Laboratory of Molecular Dermatology and Department of DermatologyRambam Medical Center
    • Rappaport Faculty of MedicineTechnion-Israel Institute of Technology
  • Reuven Bergman
    • Laboratory of Molecular Dermatology and Department of DermatologyRambam Medical Center
    • Rappaport Faculty of MedicineTechnion-Israel Institute of Technology
  • Doron Behar
    • Rappaport Faculty of MedicineTechnion-Israel Institute of Technology
  • Drora Fisher
    • Department of RadiologyShaare Zedek Medical Center
  • Derek Gordon
    • Laboratory of Statistical GeneticsRockefeller University
  • Gabriele Richard
    • Department of Dermatology and Cutaneous BiologyThomas Jefferson University
    • Laboratory of Molecular Dermatology and Department of DermatologyRambam Medical Center
    • Rappaport Faculty of MedicineTechnion-Israel Institute of Technology
Original Article

DOI: 10.1007/s00109-004-0610-8

Cite this article as:
Frishberg, Y., Topaz, O., Bergman, R. et al. J Mol Med (2005) 83: 33. doi:10.1007/s00109-004-0610-8

Abstract

Hyperphosphatemia-hyperostosis syndrome (HHS) is a rare autosomal recessive metabolic disorder characterized by elevated serum phosphate levels and repeated attacks of acute, painful swellings of the long bones with radiological evidence of periosteal reaction and cortical hyperostosis. HHS shares several clinical and metabolic features with hyperphosphatemic familial tumoral calcinosis (HFTC), which is caused by mutations in GALNT3 encoding a glycosyltransferase responsible for initiating O-glycosylation. To determine whether GALNT3 is involved in the pathogenesis of HHS we screened two unrelated Arab-Israeli HHS families for pathogenic mutations in this gene. All affected individuals harbored a homozygous splice site mutation (1524+1G↧A) in GALNT3. This mutation was previously described in a large Druze HFTC kindred and has been shown to alter GALNT3 expression and result in ppGalNAc-T3 deficiency. Genotype analysis of six microsatellite markers across the GALNT3 region on 2q24-q31 revealed that the HHS and HFTC families share a common haplotype spanning approximately 0.14 Mb. Our results demonstrate that HHS and HFTC are allelic disorders despite their phenotypic differences and suggest a common origin of the 1524+1G↧A mutation in the Middle East (founder effect). The heterogeneous phenotypic expression of the identified splice site mutation implies the existence of inherited or epigenetic modifying factors of importance in the regulation of ppGalNAc-T3 activity.

Keywords

CalcinosisPhosphateHyperostosisProximal tubule

Abbreviations

HFTC

Hyperphosphatemic familial tumoral calcinosis

HHS

Hyperphosphatemia-hyperostosis syndrome

ppGalNAc-T3

UDP-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase3

Copyright information

© Springer-Verlag 2004