Familial tumoral calcinosis(TC) is characterized by elevated serum ohosphate concentrations, normal or elevated 1.25(OH)(2) vitamin (D,) as well as periarticular and vascular calcifications. Recessive mutations in the mucin-like-glyco-syltransferase GalNAc transferase-3 (GALNT3) and the phosphaturic hormone fibroglast 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 reavealed a novel, homozygous base insertion (1102_1103insT) inGALNT3 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 onact biologically active FGF23 in TC, a comprehensive assesment 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 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. (C) 2007Wiley-Liss, Inc.