A novel CDC73 gene mutation in an Italian family with hyperparathyroidism-jaw tumour (HPT-JT) syndrome.

Purpose: The CDC73 gene, encoding parafibromin, has been identified as a tumour suppressor gene both in hyperparathyroidism-jaw tumour (HPT-JT) syndrome and in sporadic parathyroid carcinoma. While the vast majority of CDC73 mutations affect the N-terminus or the central core of the encoded protein, as yet few mutations have been reported affecting the C-terminus. Here, we report a case (Caucasian female, 28 years) with an invasive ossifying fibroma of the left mandible and hyperparathyroidism (sCa = 16 mg/dl, PTH = 660 pg/mL) due to a parathyroid lesion of 20 mm, hystologically diagnosed as carcinoma.

Methods: The whole CDC73 gene was screened for the presence of mutations by Sanger sequencing. Immunohistochemistry, in vitro functional assays, Western blotting, MTT assays and in-silico modelling were performed to assess the effect of the detected mutation.

Results: Sequence analysis of the CDC73 gene in the proband revealed the presence of a novel deletion affecting the C-terminus of the encoded protein (c.1379delT/p.L460Lfs*18). Clinical and genetic analyses of the available relatives led to the identification of three additional carriers, one of whom was also affected by a parathyroid lesion. Immunohistochemistry, Western blotting, MTT and in-silico modelling assays revealed that the deletion leads to down-regulation of the mutated protein, most likely through a proteasome-mediated pathway. We also found that the deletion may cause a conformational change in the C-terminus of the protein, possibly affecting its interaction with partner proteins. Finally, we found that the mutant protein enhances cellular growth.

Conclusions: We report a novel mutation in the CDC73 gene that may underlie HPT-JT syndrome. This mutation appears to affect the C-terminal moiety of the encoded protein, which is thought to interact with other protein partners. The identification of these partners may be instrumental for our understanding of the CDC73-associated phenotype.