Andrea Villablanca

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

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.

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

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 …

Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism.

A large number of families with familial isolated hyperparathyroidism (FIHP) have been reported. We wanted to determine if some of these families represent early manifestations of full-blown syndromes such as multiple endocrine neoplasia type 1 (MEN-1), as early identification may alter surgical and medical management. Four small families with a family history of hyperparathyroidism without clear-cut MEN-1 features were screened for a MEN1 mutation. The 10 exons of the MEN1 gene were amplified and analyzed by single-strand conformation analysis (SSCA). Abnormal SSCA shifts were then sequenced using an automated sequencer. Two germline mutations were found: R527X and P277H. The former was detected in three members of a family consisting of two children and a mother. At the time of testing the youngest son was normocalcemic and clinically normal but subsequently developed hyperparathyroidism (HPT). Since the initial testing, the family has been confirmed to be a MEN-1 family as the mother has developed abdominal pain and an elevated serum pancreatic polypeptide and the younger brother an anterior pituitary tumor and recurrent HPT. The latter P277H mutation was identified in two of three members tested from another family. Manifestations of MEN-1 syndrome have also developed. The father now has developed diarrhea and elevated serum gastrin; and the daughter has developed recurrent HPT. Genetic screening of families who clinically have FIHP is important and may influence the type of medical and surgical treatment and follow-up, as some have MEN-1 syndrome. Long-term screening for MEN syndromes should be included in this set of patients. Positive screening may predict disease and allow early detection and appropriate treatment before initiation of symptoms.

Genetic and clinical characterization of sporadic cystic parathyroid tumours

objective  The hyperparathyroidism–jaw tumour (HPT–JT) syndrome is one of the familial disorders characterized by primary hyperparathyroidism and has been linked to the chromosomal region of 1q32–q21. The parathyroid tumours related to this syndrome have shown loss of wild‐type alleles at this locus suggesting that inactivation of a tumour suppressor gene might be responsible for the disease. In the majority of these tumours cysts are a prominent feature. By loss of heterozygosity (LOH) studies, we investigated the region of interest in an attempt to clarify its possible role in a series of cystic sporadic parathyroid adenomas.

Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese

objective Multiple endocrine neoplasia type 1 (MEN1) is characterized by a triad of neoplasia affecting the parathyroid glands, enteropancreatic endocrine tissue and the anterior pituitary gland.

Molecular Genetics of Familial Hyperparathyroidism

Genetic or molecular diagnosis has not only contributed to our understanding of disease pathophysiology but also assisted in clinical diagnosis and management, especially in genetic disorders, of which familial hyperparathyroidism is a good example. We summarize here the genetic basis of familial hyperparathyroidism, which may be an associated feature of several well-known syndromes or a separate disease on its own, i.e., familial isolated hyperparathyroidism (FIHP). In FIHP, molecular diagnosis has helped to identify different entities which can be correlated to their more subtle clinical features. It is therefore important to realize that the potential of genetic tools can only be maximized if it is complemented by good and accurate clinical/pathological information.