J Korean Med Sci.  2007 Jun;22(3):560-563. 10.3346/jkms.2007.22.3.560.

A Newly Identified Insertion Mutation in the Thyroid Hormone Receptor-beta Gene in a Korean Family with Generalized Thyroid Hormone Resistance

• Kim JH
• Park TS
• Baek HS
• Kim GH
• Yoo HW
• Park JH

• KMID: 1778372
• DOI: http://doi.org/10.3346/jkms.2007.22.3.560

Abstract

Thyroid hormone resistance syndrome (RTH) is a rare disorder and is characterized by elevated levels of circulating free thyroid hormones, inappropriate secretion of thyroid stimulating hormone (TSH), and reduced peripheral tissue response to thyroid hormone. 90% of RTH subjects, when studied at the level of the gene, have been found to harbor mutations in the thyroid hormone receptor-beta(THRB) gene. These affected individuals have been shown to possess a variety of missense mutations, resulting from changes in a single nucleotide in the THRB gene that corresponds to amino acid alternation. However, insertion or deletion mutations in the THRB gene sequence are quite rare, and have been observed in only a very few cases. In this study, we describe two such cases, in which two members of the same family were determined to harbor an insertion mutation in exon 10, and had also been diagnosed with generalized RTH. This insertion mutation, specifically the insertion of a cytosine at nucleotide 1358 of the THRB gene, is, to the best of our knowledge, the first such mutation reported among RTH patients in Korea.

Keyword

Thyroid Hormone Resistance Syndrome; Thyroid Hormone Receptors Beta; Mutation

MeSH Terms

Adolescent
Adult
Child
DNA Mutational Analysis
Exons
Family Health
Female
Humans
Korea
Male
*Mutation
Thyroid Hormone Receptors beta/*genetics
Thyroid Hormone Resistance Syndrome/*genetics/therapy

Figure

• 

  Fig. 1 The sequence analysis of the thyroid hormone receptor-β (TH- RB) gene in the patient (B) and her son (C) shows an insertion of a C at position 1358/1359 in exon 10. (A) Normal control.

Reference

1. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev. 1993. 14:348–399.

2. Refetoff S, Dewind LT, De Groot LJ. Familial syndrome combining deaf-mutism, stippled epiphyses, goiter, and abnormally high PBI: Possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab. 1967. 27:279–294.

3. Refetoff S. Braverman LE, Utiger RD, editors. Resistance to thyroid hormones. The Thyroid. 2005. Philadelphia: Lippincott Williams & Wilkins;1109–1129.

4. Yen PM. Thyrotropin receptor mutations in thyroid diseases. Rev Endocr Metab Disord. 2000. 1:123–129.

5. Hwang JK, Kim KW, Kim TY, Kim SW, Park YJ, Park DJ, Kim SY, Lee HK, Cho BY. A case of syndrome of resistance to thyroid hormone associated with mutation (M313T) in thyroid hormone receptor beta gene. J Korean Soc Endocrinol. 2003. 18:206–213.

6. Yun YS, Hong SK, Ahn CW, Nam JH, Park SW, Cha BS, Song YD, Lee EJ, Lim SK, Kim KR, Lee HC, Huh KB. Mutations in thyroid hormone receptor-β associated with patients with generalized resistance and pituitary resistance to thyroid hormone. J Korean Soc Endocrinol. 2000. 15:113–120.

7. Lafranchi SH, Snyder DB, Sesser DE, Skeels MR, Singh N, Brent GA, Nelson JC. Follow-up of newborns with elevated screening T4 concentrations. J Pediatr. 2003. 143:296–301.

8. Kaplan MM, Swartz SL, Larsen PR. Partial peripheral resistance to thyroid hormone. Am J Med. 1981. 70:1115–1121.

9. Cheng SY. Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance. Trends Endocrinol Metab. 2005. 16:176–182.

10. Hodin RA, Lazar MA, Wintman BI, Darling DS, Koenig RJ, Larsen RR, Moore DD, Chin WW. Identification of a thyroid hormone receptor that is pituitary-specific. Science. 1989. 244:76–79.

11. Williams GR. Cloning and characterization of two novel thyroid hormone receptor beta isoforms. Mol Cell Bio. 2000. 20:8329–8342.

12. Sakarai A, Nakai A, De Groot LJ. Structural analysis of human thyroid normone receptor β gene. Mol Cell Endocrinol. 1990. 71:83–91.

13. Parrilla R, Mixson AJ, McPherson JA, McClaskey JH, Weintraub BD. Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain. J Clin Invest. 1991. 88:2123–2130.

14. Adams M, Matthews C, Collingwood TN, Tone Y, Beck-Peccoz P, Chatterjee KK. Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene. J Clin Invest. 1994. 94:506–515.

15. Van der Hoek YY, Mul-Steinbusch MW, Slee PH. A novel mutation (1653insC) in the thyroid hormone receptor beta in a patient resistant to thyroid hormone. Hum Mutat. 2000. 16:375.

16. Takeda K, Weiss RE, Refetoff S. Rapid localization of mutations in the thyroid hormone receptor-beta gene by denaturing gradient gel electrophoresis in 18 families with thyroid hormone resistance. J Clin Endocrinol Metab. 1992. 74:712–719.

17. Ono S, Schwartz ID, Mueller OT, Root AW, Usala SJ, Bercu BB. Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone. J Clin Endocrinol Metab. 1991. 73:990–994.

18. Takeda K, Sakurai A, DeGroot LJ, Refetoff S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-beta gene. J Clin Endocrinol Metab. 1992. 74:49–55.

19. Taniyama M, Ishikawa N, Momotani N, Ito K, Ban Y. Toxic multinodular goiter in a patient with generalized resistance to thyroid hormone who harbours the R429Q mutation in the thyroid hormone receptor β gene. Clin Endocrinol. 2001. 64:121–124.

20. Bidey SP, Hill DJ, Eggo MC. Growth factors and goitrogenesis. J Endocrinol. 1999. 160:321–332.