Two novel GALNT3 mutations in familial tumoral calcinosis.
Familial tumoral calcinosis (TC) is characterized by elevated serum phosphate concentrations, normal or elevated 1,25(OH)2 vitamin D, as well as periarticular and vascular calcifications. Recessive mutations in the mucin-like glycosyltransferase GalNAc transferase-3 (GALNT3) and the phosphaturic hormone fibroblast growth factor-23 (FGF23) have been shown to result in TC. In the present study, mutational analyses were performed on two patients with TC to determine the molecular basis of their diseases. Analysis of the first patient revealed a novel, homozygous base insertion (1102_1103insT) in GALNT3 exon 5 that results in a frameshift and premature stop codon (E375X). The second patient had a novel homozygous transition (1460 g>a) in GALNT3 exon 7, which caused a nonsense mutation (W487X). Both mutations are predicted to markedly truncate the mature GALNT3 protein product. Although the patients carry GALNT3 mutations, these individuals presented with low-normal serum concentrations of intact biologically active FGF23 and high levels of C-terminal FGF23. In order to discern a possible relationship between GALNT3 and FGF23 in TC, a comprehensive assessment of the reported TC mutations was also performed. In summary, we have detected novel GALNT3 mutations that result in familial TC, and show that disturbed serum FGF23 concentrations are present in our TC cases as well as in previously reported cases. These studies expand our current genetic understanding of familial TC, and support a pathophysiological association between GALNT3 and FGF23.
Garringer
Holly J
HJ
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, and Department of Orthopedics, Imam Khomeini University Hospital, Tehran, Iran.
Mortazavi
Seyed Mohammad Javad
SM
Esteghamat
Fatemehsadat
F
Malekpour
Mahdi
M
Boztepe
Harika
H
Tanakol
Refik
R
Davis
Siobhan I
SI
White
Kenneth E
KE
D000595:Amino Acid Sequence; D001483:Base Sequence; D002114:Calcinosis / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human