This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carling, T. Articles by Åkerström, G. Search for Related Content PubMed PubMed Citation Articles by Carling, T. Articles by Åkerström, G. Pubmed/NCBI databases OMIM Compound via MeSH Substance via MeSH Genetics Home Reference Hazardous Substances DB PARATHYROID HORMONE

Parathyroid MEN1 Gene Mutations in Relation to Clinical Characteristics of Nonfamilial Primary Hyperparathyroidism¹

Department of Surgery, Endocrine Unit, and Department of Internal Medicine (B.S.), Uppsala University Hospital, 751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Tobias Carling, Ph.D., Department of Surgery, Endocrine Unit, Uppsala University Hospital, S-751 85 Uppsala, Sweden. E-mail: tobias.carling{at}kirurgi.uu.se

Biochemical signs and severity of symptoms of primary hyperparathyroidism (pHPT) differ among patients, and little is known of any coupling of clinical characteristics of nonfamilial pHPT to genetic abnormalities in the parathyroid tumors. Mutations in the recently identified MEN1 gene at chromosome 11q13 have been found in parathyroid tumors of nonfamilial pHPT. Using microsatellite analysis for loss of heterozygosity (LOH) at 11q13 and DNA sequencing of coding exons, the MEN1 gene was studied in 49 parathyroid lesions of patients with divergent symptoms, operative findings, histopathological diagnosis, and biochemical signs of nonfamilial pHPT. Allelic loss at 11q13 was detected in 13 tumors, and 6 of them demonstrated previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of the detected mutations would most likely result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and biochemical characteristics of HPT were apparently unrelated to the presence or absence of LOH and the MEN1 gene mutations. However, the demonstration of LOH at 11q13 and MEN1 gene mutations in small parathyroid adenomas of patients with slight hypercalcemia and normal serum PTH levels suggest that altered MEN1 gene function may also be important for the development of mild sporadic pHPT.

This article has been cited by other articles:

				V. M. Howell, J. W. Cardinal, A.-L. Richardson, O. Gimm, B. G. Robinson, and D. J. Marsh Rapid Mutation Screening for HRPT2 and MEN1 Mutations Associated with Familial and Sporadic Primary Hyperparathyroidism J. Mol. Diagn., November 1, 2006; 8(5): 559 - 566. [Abstract] [Full Text] [PDF]

				G. J. Strewler A 64-Year-Old Woman With Primary Hyperparathyroidism JAMA, April 13, 2005; 293(14): 1772 - 1779. [Full Text] [PDF]

				H. Sowa, H. Kaji, R. Kitazawa, S. Kitazawa, T. Tsukamoto, S. Yano, T. Tsukada, L. Canaff, G. N. Hendy, T. Sugimoto, et al. Menin Inactivation Leads to Loss of Transforming Growth Factor {beta} Inhibition of Parathyroid Cell Proliferation and Parathyroid Hormone Secretion Cancer Res., March 15, 2004; 64(6): 2222 - 2228. [Abstract] [Full Text] [PDF]

				V M Howell, C J Haven, K Kahnoski, S K Khoo, D Petillo, J Chen, G J Fleuren, B G Robinson, L W Delbridge, J Philips, et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours J. Med. Genet., September 1, 2003; 40(9): 657 - 663. [Abstract] [Full Text] [PDF]

				S. M. Mallya, J. J. Gallagher, and A. Arnold Analysis of Microsatellite Instability in Sporadic Parathyroid Adenomas J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1248 - 1251. [Abstract] [Full Text] [PDF]

				T. Dwight, A. E. Nelson, G. Theodosopoulos, A. L. Richardson, D. L. Learoyd, J. Philips, L. Delbridge, J. Zedenius, B. T. Teh, C. Larsson, et al. Independent Genetic Events Associated with the Development of Multiple Parathyroid Tumors in Patients with Primary Hyperparathyroidism Am. J. Pathol., October 1, 2002; 161(4): 1299 - 1306. [Abstract] [Full Text] [PDF]

				T. M. Shattuck, J. Costa, M. Bernstein, R. T. Jensen, D. C. Chung, and A. Arnold Mutational Analysis of Smad3, a Candidate Tumor Suppressor Implicated in TGF-{beta} and Menin Pathways, in Parathyroid Adenomas and Enteropancreatic Endocrine Tumors J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3911 - 3914. [Abstract] [Full Text] [PDF]

				E. Szabo, T. Carling, O. Hessman, and J. Rastad Loss of Heterozygosity in Parathyroid Glands of Familial Hypercalcemia with Hypercalciuria and Point Mutation in Calcium Receptor J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3961 - 3965. [Abstract] [Full Text] [PDF]

				Y. Imanishi, H. Tahara, N. Palanisamy, S. Spitalny, I. B. Salusky, W. Goodman, M. L. Brandi, T. B. Drueke, E. Sarfati, P. Urena, et al. Clonal Chromosomal Defects in the Molecular Pathogenesis of Refractory Hyperparathyroidism of Uremia J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1490 - 1498. [Abstract] [Full Text] [PDF]

				S. S. Guo and M. P. Sawicki Molecular and Genetic Mechanisms of Tumorigenesis in Multiple Endocrine Neoplasia Type-1 Mol. Endocrinol., October 1, 2001; 15(10): 1653 - 1664. [Abstract] [Full Text] [PDF]

				C. A. Stratakis, D. H. Schussheim, S. M. Freedman, M. F. Keil, S. D. Pack, S. K. Agarwal, M. C. Skarulis, R. J. Weil, I. A. Lubensky, Z. Zhuang, et al. Pituitary Macroadenoma in a 5-Year-Old: An Early Expression of Multiple Endocrine Neoplasia Type 1 J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4776 - 4780. [Abstract] [Full Text]

				H. Tahara, Y. Imanishi, T. Yamada, Y. Tsujimoto, T. Tabata, T. Inoue, M. Inaba, H. Morii, and Y. Nishizawa Rare Somatic Inactivation of the Multiple Endocrine Neoplasia Type 1 Gene in Secondary Hyperparathyroidism of Uremia J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4113 - 4117. [Abstract] [Full Text]

				S. Uchino, S. Noguchi, M. Sato, H. Yamashita, H. Yamashita, S. Watanabe, T. Murakami, M. Toda, A. Ohshima, T. Futata, et al. Screening of the MEN1 Gene and Discovery of Germ-Line and Somatic Mutations in Apparently Sporadic Parathyroid Tumors Cancer Res., October 1, 2000; 60(19): 5553 - 5557. [Abstract] [Full Text]

				T. Carling, J. Rastad, E. Szabó, G. Westin, and G. Åkerström Reduced Parathyroid Vitamin D Receptor Messenger Ribonucleic Acid Levels in Primary and Secondary Hyperparathyroidism J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2000 - 2003. [Abstract] [Full Text]

				S. B. Brown, T. T. Brierley, N. Palanisamy, I. B. Salusky, W. Goodman, M. L. Brandi, T. B. Drüeke, E. Sarfati, P. Ureña, R. S. K. Chaganti, et al. Vitamin D Receptor as a Candidate Tumor-Suppressor Gene in Severe Hyperparathyroidism of Uremia J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 868 - 872. [Abstract] [Full Text]

				F. Farnebo, S. Kytola, B. T. Teh, T. Dwight, F. K. Wong, A. Hoog, M. Elvius, W. S. Wassif, N. W. Thompson, L.-O. Farnebo, et al. Alternative Genetic Pathways in Parathyroid Tumorigenesis J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3775 - 3780. [Abstract] [Full Text] [PDF]