FTC (OMIM #211900) is a rare autosomal recessive disorder characterized by the presence of ectopic calcifications in the skin and subcutaneous tissues. These calcified masses look like irregular tumors which usually develop in a periarticular position, causing pain and often necessitating surgical excision. The majority of affected individuals have hyperphosphatemia due to increased renotubular reabsorption of phosphate and elevated levels of serum 1,25-dihydroxyvitamin D (calcitriol), while calcium and parathyroid hormone (PTH) levels are normal. Recently, biallelic mutations in the GALNT3 (UDP-N-acetyl-α-D-galactosamine/polypeptide N-acetylgalactosaminyl transferase 3) gene have been identified in 3 families with FTC. GALNT3 encodes a biosynthetic enzyme which initiates mucin-type O-glycosylation. In the present study we performed mutation analysis of the GALNT3 gene in a subject with FTC and in his relatives. The proband showed the classical manifestations of the disease, including ectopic periarticular calcifications and hyperphosphatemia. Starting from the first decade of life he developed massive semicalcific lesions and underwent numerous surgeries to remove calcified deposits. Direct sequencing of genomic fragments corresponding to all GALNT3 coding exons, as well as conserved splice junctions, revealed that the proband was a compound heterozygote for two novel nonsense mutations in exon 4 and in exon 7. Both mutations cause premature termination of protein translation. Probands parents and his sibs are carriers of one of the two mutations. In order to verify cosegregation of the mutations with the disease, PCR-RFLP analysis was performed for this family, confirming the results of the mutation analysis. These are the first mutations identified in the GALNT3 gene in an Italian family. Additional studies are needed to elucidate the role of this enzyme during O-glycosylation and to clarify why its impairment causes FTC.
01 - 05 Apr 2006
European Society of Endocrinology