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- Title
Identification of a recurrent mutation inGALNT3demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders.
- Authors
Frishberg, Yaacov; Topaz, Orit; Bergman, Reuven; Behar, Doron; Fisher, Drora; Gordon, Derek; Richard, Gabriele; Sprecher, Eli
- 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 inGALNT3encoding a glycosyltransferase responsible for initiating O-glycosylation. To determine whetherGALNT3is 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) inGALNT3. This mutation was previously described in a large Druze HFTC kindred and has been shown to alterGALNT3expression and result in ppGalNAc-T3 deficiency. Genotype analysis of six microsatellite markers across theGALNT3region 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.
- Subjects
EXOSTOSIS; METABOLIC disorders; CARCINOGENESIS; VIRAL carcinogenesis; ALLELES; BONE disease genetics
- Publication
Journal of Molecular Medicine, 2005, Vol 83, Issue 1, p33
- ISSN
0946-2716
- Publication type
Article
- DOI
10.1007/s00109-004-0610-8