Endocrine Abstracts

Parathyroid tumours occurring in association with ossifying fibromas of the jaw are the hallmarks of the hyperparathyroidism-jaw tumour (HPT-JT) syndrome, which is inherited as an autosomal dominant trait. The HPT-JT gene, which is located on chromosome 1q25, consists of 17 exons and encodes a 531 amino acid protein named PARAFIBROMIN (Nature Genetics, in press). The observation of loss of heterozygosity (LOH) involving 1q25 in HPT-JT parathyroid tumours and the detection of inactivating germline mutations in patients suggests that this gene acts as a tumour suppressor, in keeping with the Knudson 'two-hit' model of hereditary cancer. However, this represents only one mechanism by which the second hit may occur, and the other mechanisms, such as intragenic deletions or point mutations that inactivate the gene, have not been reported in these tumours. We have therefore undertaken studies to search for such abnormalities in 4 HPT-JT parathyroid tumours (two from related individuals) that did not have LOH at 1q25. DNA sequence analysis was used to search for PARAFIBROMIN mutations and two sequence polymorphisms in introns 2 and 7 were used to search for intragenic deletions. This revealed the presence of the 3 expected germline mutations, that were deletions (30delG, 356delA and 765delTG), and one tumour also had a somatic mutation which consisted of a T to C transition in codon 95. This abnormality, which was not observed in 110 alleles from normal individuals, is predicted to alter an evolutionary conserved leucine to a proline and is thus likely to disrupt the structure of PARAFIBROMIN. Intragenic deletions were not observed. Thus, our results, which are the first to identify the combined occurrence of somatic and germline PARAFIBROMIN mutations (i.e. the 'two-hits') in one parathyroid tumour, are consistent with a tumour suppressor role for the HPT-JT gene.