title: Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders.
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.
authors.affiliation: Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Frishberg
authors.forename: Orit
authors.initials: O
authors.lastname: Topaz
authors.forename: Reuven
authors.initials: R
authors.lastname: Bergman
authors.forename: Doron
authors.initials: D
authors.lastname: Behar
authors.forename: Drora
authors.initials: D
authors.lastname: Fisher
authors.forename: Derek
authors.initials: D
authors.lastname: Gordon
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
mesh_terms: D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002648:Child; D002762:Cholecalciferol / Q000378:metabolism; D005260:Female; D006239:Haplotypes; D006801:Humans; D015576:Hyperostosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D010018:Osteomalacia / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D010375:Pedigree; D010710:Phosphates / Q000097:blood*; D017422:Sequence Analysis, DNA; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D002118:Calcium; D002762:Cholecalciferol; D017350:N-Acetylgalactosaminyltransferases; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D010710:Phosphates; D000097763:Polypeptide N-acetylgalactosaminyltransferase