Endocrine Abstracts

Mutations of parafibromin, which is a 531 amino acid protein, are associated with the hyperparathyroidism-jaw tumour (HPT-JT) syndrome. HPT-JT is an autosomal dominant disease that is characterised by the occurrence of parathyroid tumours, which are commonly malignant, and ossifying fibromas of the jaw bones. To date 13 different inactivating germline mutations (3 nonsense, 9 frameshift and one missense altering the initiation codon) of PARAFIBROMIN have been identified in HPT-JT families (Nature Genetics, December 2002). We have searched for such PARAFIBROMIN mutations in 2 patients, one of whom had HPT-JT, and the other had a parathyroid carcinoma and a family history of primary hyperparathyroidism. Leukocyte DNA samples from these 2 patients and an unrelated normocalcaemic individual were used with 17 pairs of oligonucleotide primers to amplify the entire 1596bp coding region of the gene. The DNA sequences of both strands of the PCR products were then determined. This revealed a C to T transition in codon 234 that resulted in a nonsense mutation (Arg234Stop) in the HPT-JT patient, and a g to a transition involving the invariant gt dinucleotide of the consensus donor splice site of intron 1 in the patient with the parathyroid carcinoma. Both of these abnormalities were absent in 55 unrelated normocalcaemic individuals, thereby indicating that these are likely to be significant mutations. Furthermore, the nonsense mutation involves the alteration of an evolutionarily conserved Arg residue, and the donor splice site mutation is predicted to lead to the retention of intron 1 with a premature stop codon that results in a truncated protein of 44 amino acids. Thus, we have identified two novel germline PARAFIBROMIN mutations, one of which represents the first donor splice site mutation to be detected. In addition, our results suggest that PARAFIBROMIN mutations may have a role in the causation of parathyroid carcinomas.