Identification of a recurrent mutation in
GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders |
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Authors: | Yaacov Frishberg Orit Topaz Reuven Bergman Doron Behar Drora Fisher Derek Gordon Gabriele Richard Eli Sprecher |
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Institution: | (1) Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel;(2) Laboratory of Molecular Dermatology and Department of Dermatology, Rambam Medical Center, Haifa, Israel;(3) Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel;(4) Department of Radiology, Shaare Zedek Medical Center, Jerusalem, Israel;(5) Laboratory of Statistical Genetics, Rockefeller University, New York, NY, USA;(6) Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA |
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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.An erratum to this article can be found at |
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Keywords: | Calcinosis Phosphate Hyperostosis Proximal tubule |
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