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HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome

Abstract

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.

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Figure 1: Genetic analysis of kindreds affected with HPT–JT and partial transcript map of the critical region.
Figure 2: Mutations in kindreds affected with HPT–JT.

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Acknowledgements

We gratefully acknowledge the selfless participation of the family members in these studies; the hours of clinical time devoted to these studies by M. Leppert, G. Pidwerny, O.H. Clark, S. Kytölä, E. Korpi-Hyövälti, C.J. Lips, L.E. Mallette, R. van der Luijt, G.J. Fleuren, L. Barros, V. Leite, M.M. Loureiro, M.C. Pereira, L. Ruas, J. Sampson, M.A. Santos, L.G. Sobrinho, A. Hattersley, R. Paisley, M.H. Wheeler, G. Talpos, I. Salti, D. Firat, M.C. Skarulis and N. Thompson; and the expert technical assistance of K. Dietrich, A. Pole, C. Markey, D. F.-Lutz, M.C. Jackson, E. Eddings, G.D. Tran, J. Booth, A.N. Tkachuk and J. Mestre. This work was supported in part by grants from The Swedish Cancer Foundation, the Torsten and Ragnar Söderberg Foundations, the Cornell Foundation and the Gustav V Jubilee Foundation (C.L.), US National Institutes of Health, US National Center for Research Resources Public Health Service Research Grant, the American Cancer Society (M.R.H.), The Dykstra Foundation and the US Public Health Service (C.E.J.), Medical Research Council, U.K. (A.M.K., P.D.L., B.H., A.A.P. and R.V.T.), Rhodes Trust, U.K. (P.D.L.) and Liga Portuguesa Confra o Cancro Instituto Portugues de Oncologia de Francisco Gentil, Portugal (B.M.C.).

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Correspondence to J.D. Carpten or C. Larsson.

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Carpten, J., Robbins, C., Villablanca, A. et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome. Nat Genet 32, 676–680 (2002). https://doi.org/10.1038/ng1048

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