HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.
Carpten JD., Robbins CM., Villablanca A., Forsberg L., Presciuttini S., Bailey-Wilson J., Simonds WF., Gillanders EM., Kennedy AM., Chen JD., Agarwal SK., Sood R., Jones MP., Moses TY., Haven C., Petillo D., Leotlela PD., Harding B., Cameron D., Pannett AA., Höög A., Heath H., James-Newton LA., Robinson B., Zarbo RJ., Cavaco BM., Wassif W., Perrier ND., Rosen IB., Kristoffersson U., Turnpenny PD., Farnebo L-O., Besser GM., Jackson CE., Morreau H., Trent JM., Thakker RV., Marx SJ., Teh BT., Larsson C., Hobbs MR.
We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.