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J Med Genet 41:e32 doi:10.1136/jmg.2003.012369
  • Online mutation report

Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP)

  1. A Villablanca1,2,
  2. A Calender3,
  3. L Forsberg1,
  4. A Höög2,
  5. J-D Cheng4,
  6. D Petillo4,
  7. C Bauters5,
  8. K Kahnoski4,
  9. T Ebeling6,
  10. P Salmela6,
  11. A-L Richardson7,
  12. L Delbridge7,
  13. A Meyrier8,
  14. C Proye9,
  15. J D Carpten10,
  16. B T Teh4,
  17. B G Robinson7,
  18. C Larsson1
  1. 1Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
  2. 2Department of Oncology-Pathology, Karolinska Hospital, Stockholm, Sweden
  3. 3Laboratoire de Génétique et Cancer, UMR CNRS, Lyon, France
  4. 4Van Andel Research Institute, Grand Rapids, Michigan, USA
  5. 5Service d’Endocrinologie, CHRU de Lille, Lille, France
  6. 6Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
  7. 7Cancer Genetics Unit, Kolling Institute of Medical Research, Royal North Shore Hospital and the Department of Molecular Medicine, University of Sydney, Sydney, Australia
  8. 8Service de Néphrologie, Hôpital Broussais, Paris, France
  9. 9Service de Chirurgie Endocrine, CHRU de Lille, Lille, France
  10. 10Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA
  1. Correspondence to:
 A Villablanca
 Departments of Molecular Medicine and Oncology-Pathology, Karolinska Hospital, Stockholm, Sweden; andrea.villablancacmm.ki.se
  • Received 3 October 2003
  • Accepted 6 October 2003

Familial forms of primary hyperparathyroidism (PHPT) constitute a broad group of disorders in which PHPT is either a main or an associated feature. With the advances in disease gene identification, some of the genetic abnormalities underlying familial PHPT have been clarified.1,2 In hyperparathyroidism–jaw tumour syndrome (HPT-JT; OMIM #145001) the affected family members frequently develop PHPT, ossifying jaw fibromas, and cystic and neoplastic renal lesions.3–6 A typical feature of HPT-JT is adenomas and carcinomas of the parathyroid glands, which often have cystic features.1 This is in contrast to the other forms of familial PHPT in which the parathyroid tumours are generally benign.

The disease locus was first mapped to chromosomal region 1q25–q32 by linkage in affected families3,5–7 and recently the causal HRPT2 gene was isolated through a positional cloning approach.3 The HRPT2 gene consists of 17 exons encoding an evolutionarily well conserved, 531 amino acid protein named parafibromin. The inactivating mutations demonstrated in the germline of HPT-JT kindreds and as somatic events in some sporadic parathyroid adenomas3 are in agreement with the observations of somatic loss of the wild type alleles,6 suggesting that parafibromin has a tumour suppressor function.3,6

The importance of the multiple endocrine neoplasia type 1 gene (MEN1) in familial PHPT has been well established. MEN1 is a tumour suppressor gene located in 11q13,8–10 and its encoded protein menin has been shown to interact with several proteins involved in transcriptional regulation.11,12 The MEN1 syndrome (OMIM #131100) is clinically characterised by the frequent development of tumours in the parathyroids, the endocrine pancreas and duodenum, and the anterior pituitary gland. MEN1, which is the most common form of hereditary PHPT, is caused by germline mutations of MEN1, both in the form of inherited …