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

Yaacov Frishberg, Orit Topaz, Reuven Bergman, Doron Behar, Drora Fisher, Derek Gordon, Gabriele Richard, Eli Sprecher

Research output: Contribution to journalArticle

86 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)33-38
Number of pages6
JournalJournal of Molecular Medicine
Volume83
Issue number1
DOIs
StatePublished - Jan 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Keywords

  • Calcinosis
  • Hyperostosis
  • Phosphate
  • Proximal tubule

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