This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart 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 Gabriel, E. M. Articles by Morris, J. C. Search for Related Content PubMed PubMed Citation Articles by Gabriel, E. M. Articles by Morris, J. C.

Germline Polymorphism of Codon 727 of Human Thyroid-Stimulating Hormone Receptor Is Associated with Toxic Multinodular Goiter¹

Division of Endocrinology and Department of Surgery, Mayo Clinic and Medical School, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Dr. John C. Morris, Division of Endocrinology, Mayo Clinic and Medical School, Rochester, Minnesota 55905.

Toxic multinodular goiter (TMNG) represents a frequent cause of endogenous hyperthyroidism, affecting 5–15% of such patients (with higher frequencies reported in iodine-deficient areas of the world). Although mutations of human TSH receptor (hTSHR) have been described in autonomously functioning thyroid nodules (AFTN), the role of such mutations in the pathogenesis of TMNG remains unclear. To search for alterations of hTSHR in AFTN and TMNG, we performed bidirectional, dye primer automated fluorescent DNA sequencing of the entire transmembrane domain and cytoplasmic tail of hTSHR (TMD+CT-hTSHR) using DNA extracted from nodular regions of 24 patients with TMNG and 7 patients with AFTN. Eight of the 24 patients (33.3%) showed heterozygote polymorphism of codon 727 on the cytoplasmic tail of hTSHR with an amino acid substitution of aspartic acid to glutamic acid. Three of 24 (12.5%) patients with TMNG were found to carry a heterozygote mutation of codon 703, resulting in substitution of alanine with glycine. One patient had multiple heterozygote mutations including I606M (Ile to Met), A703G (Ala to Gly), Q720E (Gln to Glu), and D727E (Asp to Glu). Two patients exhibited silent polymorphism of codons 460 and 618. We found no mutation of the TMD+CT-hTSHR in 7 patients with AFTN, except for a silent polymorphism of codon 460 in 1. DNA fingerprinting of codon 727 using restriction enzyme NlaIII and genomic DNA confirmed the sequencing results in all cases, indicating that the sequence alterations were not somatic in nature. This technique was also used to examine peripheral blood genomic DNA from 52 normal individuals and 49 patients with Graves’ disease; 33.3% of TMNG (P = 0.019 vs. normal subjects), 16.3% of Graves’ disease patients (P = 0.10 vs. normal subjects), and 9.6% of normal individuals were heterozygous for the D727E polymorphism. Expression of the D727E hTSHR variant in eukaryotic cells (COS-7) resulted in an exaggerated cAMP response to TSH stimulation compared to that of the wild-type hTSHR. These findings indicate that a germline polymorphism of codon D727E of hTSHR is associated with TMNG, suggesting that its presence is an important predisposing genetic factor in the pathogenesis of TMNG.

This article has been cited by other articles:

				R. P Peeters, W. M van der Deure, and T. J Visser Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases. Eur. J. Endocrinol., November 1, 2006; 155(5): 655 - 662. [Abstract] [Full Text] [PDF]

				K. Krohn, D. Fuhrer, Y. Bayer, M. Eszlinger, V. Brauer, S. Neumann, and R. Paschke Molecular Pathogenesis of Euthyroid and Toxic Multinodular Goiter Endocr. Rev., June 1, 2005; 26(4): 504 - 524. [Abstract] [Full Text] [PDF]

				H. Hiratani, D. W. Bowden, S. Ikegami, S. Shirasawa, A. Shimizu, Y. Iwatani, and T. Akamizu Multiple SNPs in Intron 7 of Thyrotropin Receptor Are Associated with Graves' Disease J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2898 - 2903. [Abstract] [Full Text] [PDF]

				A. Matakidou, N. Hamel, S. Popat, K. Henderson, T. Kantemiroff, C. Harmer, S. E.M. Clarke, R. S. Houlston, and W. D. Foulkes Risk of non-medullary thyroid cancer influenced by polymorphic variation in the thyroglobulin gene Carcinogenesis, March 1, 2004; 25(3): 369 - 373. [Abstract] [Full Text] [PDF]

				R. P. Peeters, H. van Toor, W. Klootwijk, Y. B. de Rijke, G. G. J. M. Kuiper, A. G. Uitterlinden, and T. J. Visser Polymorphisms in Thyroid Hormone Pathway Genes Are Associated with Plasma TSH and Iodothyronine Levels in Healthy Subjects J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2880 - 2888. [Abstract] [Full Text] [PDF]

				K. Krohn and R. Paschke Progress in Understanding the Etiology of Thyroid Autonomy J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3336 - 3345. [Full Text] [PDF]

				M. Tonacchera and A. Pinchera Thyrotropin Receptor Polymorphisms and Thyroid Diseases J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2637 - 2639. [Full Text]

				M. Tonacchera, P. Agretti, L. Chiovato, V. Rosellini, G. Ceccarini, A. Perri, P. Viacava, A. G. Naccarato, P. Miccoli, A. Pinchera, et al. Activating Thyrotropin Receptor Mutations Are Present in Nonadenomatous Hyperfunctioning Nodules of Toxic or Autonomous Multinodular Goiter J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2270 - 2274. [Abstract] [Full Text]