Skip to main content
SpringerLink
Log in

TGB Deficiency: description of two novel mutations associated with complete TBG deficiency and review of the literature

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Thyroxine-binding globulin (TBG) is the main thyroid hormone transport protein in serum. Inherited TBG defects lead to a complete (TBG-CD) or a partial (TBG-PD) deficiency and have a diagenic transmission, being clinically fully expressed only in hemizygous males and in homozygous females. In the present study, seven patients from two unrelated families with TBG-CD were studied and two novel TBG mutations were documented. In particular, a T insertion at the 5′ donor splice site of exon 0, between nucleotides 2 and 3 at the beginning of intron 1 (g.IVS1+2_3insT) was found in one family and was named TBG-Milano. The other novel mutation is a T deletion at nucleotide 214 of exon 1, which leads to a frameshift at codon 50 with a premature stop codon at position 51 (c.214delT, P50fsX51) and was named TBG-Nikita. According to the X-linked transmission of the defect, females harboring the mutation showed a reduction in TBG levels with normal TSH and total thyroid hormone values at the lower limit of normal. Males harboring either TBG-Milano or TBG-Nikita, showed normal TSH values and low levels of total thyroid hormones and lacked TBG. In conclusion, we report two novel mutations of the TBG gene associated with a complete TBG defect. The first mutation lies at the 5′ donor splice site of exon 0 and probably alters the start of translation, while the second is a single nucleotide deletion and leads to a premature stop codon.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Refetoff S, Larsen R (1989) Transport, cellular uptake, and metabolism of thyroid hormone. In: DeGroot LJ (ed) Endocrinology, 2nd edn. Saunders Elsevier, Philadelphia, pp 541–561

    Google Scholar 

  2. Hayashi Y, Mori Y, Janssen OE, Sunthornthepvarakul T, Weiss RE, Takeda K, Weinberg M, Seo H, Bell GI, Refetoff S (1993) Human thyroxine-binding globulin gene: complete sequence and transcriptional regulation. Mol Endocrinol 7:1049–1060

    Article  PubMed  CAS  Google Scholar 

  3. Flink IL, Bailey TJ, GUstavson TA, Markham BE, Morkin E (1986) Complete amino acid sequence of humane thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiprotease. Proc Natl Acad Sci USA 83:7708–7712

    Article  PubMed  CAS  Google Scholar 

  4. Trent JM, Flink IL, Morkin E, Van Tuinen P, Ledbetter DH (1987) Localization of the human thyroxine-binding globulin gene to the long arm of the X-chromosome (Xq21–22). Am J Hum Genet 94:428–435

    Google Scholar 

  5. Refetoff S (1989) Inherited thyroxine-binding globulin abnormalities in man. Endocr Rev 10:275–293

    PubMed  CAS  Google Scholar 

  6. Lyon MF (1961) Genetic, gene action in the X-chromosome of the mouse (Mus musculus L). Nature 190:372–373

    Article  PubMed  CAS  Google Scholar 

  7. Okamoto H, Mori Y, Tani Y, Nakagomi Y, Sano T, Ohyama K, Saito H, Oiso Y (1996) Molecular analysis of females manifesting thyroxine-binding globulin (TBG) deficiency: selective X-chromosome inactivation responsible for the difference between phenotype and genotype in TBG-deficient females. J Clin Endocrinol Metab 81:2204–2208

    Article  PubMed  CAS  Google Scholar 

  8. Mori Y, Seino S, Takeda K, Flink IL, Murata Y, Bell GI, Refetoff S (1989) A mutation causing reduced biological activity and stability of thyroxine-binding globulin probably as a result of abnormal glycosylation of the molecule. Mol Endocrinol 3:575–579

    Article  PubMed  CAS  Google Scholar 

  9. Takeda K, Mori Y, Sobieszczyk S, Seo H, Dick M, Watson F, Flink IL, Seino S, Bell GI, Refetoff S (1989) Sequence of the variant thyroxine-binding globulin of Australian aborigines: only one of the two amino acid replacements is responsible for its altered properties. J Clin Invest 83:1344–1348

    Article  PubMed  CAS  Google Scholar 

  10. Mori Y, Takeda K, Charbonneau M, Refetoff S (1990) Replacement of Leu227 by Pro in thyroxine-binding globulin (TBG) is associated with complete TBG deficiency in three out of eight families with this inherited defect. J Clin Endocrinol Metab 70:804–809

    PubMed  CAS  Google Scholar 

  11. Waltz MR, Pullman TN, Takeda K, Sobieszczyk P, Refetoff S (1990) Molecular basis for the properties of the thyroxine-binding globulin-slow variant in American blacks. J Endocrinol Invest 13:343–349

    PubMed  CAS  Google Scholar 

  12. Bertenshaw R, Takeda K, Refetoff S (1991) Sequencing of the variant thyroxine-binding globulin (TBG)-Quebec reveals two nucleotides substitutions. Am J Hum Genet 48:741–744

    PubMed  CAS  Google Scholar 

  13. Li P, Janssen OE, Takeda K, Bertenshaw RH, Refetoff S (1991) Complete thyroxine-binding globulin (TBG) deficiency caused by a single nucleotide deletion in the TBG gene. Metabolism 40:1231–1234

    Article  PubMed  CAS  Google Scholar 

  14. Janssen OE, Takeda K, Refetoff S (1991) Sequence of the variant thyroxine-binding globulin (TBG) in a Montreal family with partial TBG deficiency. Hum Genet 87:119–122

    Article  PubMed  CAS  Google Scholar 

  15. Yamamori I, Mori Y, Seo H, Hirooka Y, Imamura S, Miura Y, Matsui N, Oiso Y (1991) Nucleotide deletion resulting in a frameshift as a possible cause of complete thyroxine-binding globulin deficiency in six Japanese families. J Clin Endocrinol Metab 73:262–267

    PubMed  CAS  Google Scholar 

  16. Bertenshaw R, Sarne D, Tornari J, Weinberg M, Refetoff S (1992) Sequencing of the variant thyroxine-binding globulin (TBG)-San Diego reveals two nucleotide substitutions. Biochim Biophys Acta 1139:307–310

    PubMed  CAS  Google Scholar 

  17. Shirotani T, Kishikawa H, Wake N, Miyamura N, Hashimoto Y, Motoyoshi S, Yamaguchi K, Shichiri M (1992) Thyroxine-binding globulin variant (TBG-Kumamoto): identification of a point mutation and genotype analysis of its family. Endocrinol Jpn 39:577–584

    PubMed  CAS  Google Scholar 

  18. Miura Y, Mori Y, Kambe F, Tani Y, Oiso Y, Seo H (1994) Impaired intracellular transport contributes to partial thyroxine-binding globulin deficiency in a Japanese family. J Clin Endocrinol Metab 79:740–744

    Article  PubMed  CAS  Google Scholar 

  19. Janssen OE, Chen B, Buttner C, Refetoff S, Scriba PC (1995) Molecular and structural characterization of the heat-resistant thyroxine-binding globulin-Chicago. J Biol Chem 270:28234–28238

    Article  PubMed  CAS  Google Scholar 

  20. Ueta Y, MitaniY, Yioshida A, Taniguchi S, Mori A, Hattori K, Hisatome I, Manabe I, Takeda K, Sato R, Ahmmed GU, Tsuboi M, Ohtahara A, Hiroe K, Tanaka Y, Shigemasa C (1997) A novel mutation causing complete deficiency of thyroxine binding globulin. Clin Endocrinol 47:1–5

    Article  CAS  Google Scholar 

  21. Carvalho GA, Weiss RE, Vladutiu AO, Refetoff S (1998) Complete deficiency of thyroxine-binding globulin (TBG-CD Buffalo) caused by a new nonsense mutation in the thyroxine-binding globulin gene. Thyroid 8:161–165

    Article  PubMed  CAS  Google Scholar 

  22. Carvalho GA, Weiss RE, Refetoff S (1998) Complete thyroxine-binding globulin (TBG) deficiency produced by a mutation in acceptor splice site causing frameshift and early termination of translation (TBG-Kantakee). J Clin Endocrinol Metab 83:3604–3608

    Article  PubMed  CAS  Google Scholar 

  23. Miura Y, Hershkovitz E, Inagaki A, Parvari R, Oiso Y, Phillip M (2000) A novel mutation causing complete thyroxine-binding globulin deficiency (TBG-CD-Negev) among the Bedouins in southern Israel. J Clin Endocrinol Metab 85:3687–3689

    Article  PubMed  CAS  Google Scholar 

  24. Reutrakul S, Janssen OE, Refetoff S (2001) Three novel mutations causing complete T4-binding globulin deficiency. J Clin Endocrinol Metab 86:5039–5044

    Article  PubMed  CAS  Google Scholar 

  25. Domingues R, Bugalho MJ, Garrao A, Boavida JM, Sobrinho L (2002) Two novel variants in the thyroxine-binding globulin (TBG) gene behind the diagnosis of TBG deficiency. Eur J Endocrinol 146:485–490

    Article  PubMed  CAS  Google Scholar 

  26. Reutrakul S, Dumitresku A, Macchia PE, Moll GW Jr, Vierhapper H, Refetoff S (2002) Complete thyroxine-binding globulin (TBG) deficiency in two families without mutations in coding or promoter region of the TBG gene: In vitro demonstration of exon skipping. J Clin Endocrinol Metab 87:1045–1051

    Article  PubMed  CAS  Google Scholar 

  27. Su Ching-Chien, Wu YC, Chiu CY, Won JG, Jap TS (2003) Two novel mutations in the gene encoding thyroxine-binding globulin (TBG) as a cause of complete TBG deficiency in Taiwan. Clin Endocrinol 58:409–414

    Article  CAS  Google Scholar 

  28. Fingerhut A, Reutrakul S, Knuedeler SD, Moeller LC, Greenlee C, Refetoff S, Janssen OE (2004) Partial deficiency of thyroxine-binding globulin-Allentown is due to a mutation in the signal peptide. J Clin Endocrinol Metab 89:2477–2483

    Article  PubMed  CAS  Google Scholar 

  29. Murata Y, Mori Y, Miura Y (1994) Inherited abnormality of thyroxine-binding globulin: its gene abnormality and pathogenesis. Nippon Rinsho 52:880–885

    PubMed  CAS  Google Scholar 

  30. Mori Y, Jing P, Kayama M, Fujieda K, Hasegawa T, Nogimori T, Hirooka Y, Mitsuma T (1999) Gene amplification as a common cause of inherited thyroxine-binding globulin excess: analysis of one familial and two sporadic cases. Endocr J 46:613–619

    PubMed  CAS  Google Scholar 

  31. Mandel S, Hanna C, Boston B, Sesser D, LaFranchi S (1993) Thyroxine-binding globulin deficiency detected by newborn screening. J Pediatr 122:227–230

    PubMed  CAS  Google Scholar 

  32. Yamamori I, Mori Y, Miura Y, Tani Y, Imamura S, Oiso Y, Seo H (1993) Gene screening of 23 Japanese families with complete thyroxine-binding globulin deficiency: identification of a nucleotide deletion at codon 352 as a common cause. Endocr J 40:563–569

    PubMed  CAS  Google Scholar 

  33. Takeda K, Iyota K, Mori Y, Tamura Y, Suehiro T, Kubo Y, Refetoff S, Hashimoto K (1994) Gene screening in Japanese families with complete deficiency of thyroxine-binding globulin demonstrates that a nucleotide deletion at codon 352 may be a race specific mutation. Clin Endocrinol 40:221–226

    CAS  Google Scholar 

  34. Murata Y, Takamatsu J, Refetoff S (1986) Inherited abnormality of thyroxine-binding globulin with no demonstrable thyroxine-binding activity and high serum levels of denatured thyroxine-binding globulin. N Engl J Med 314:694–699

    Article  PubMed  CAS  Google Scholar 

  35. Krawczak M, Reiss J, Cooper DN (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 90:41–54

    Article  PubMed  CAS  Google Scholar 

  36. Cooper DN, Ball EV, Krawczak M (1998) The human gene mutation database. Nucleic Acids Res 26:285–287

    Article  PubMed  CAS  Google Scholar 

  37. Shapiro MB, Senapathy P (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15:7155–7174

    PubMed  CAS  Google Scholar 

  38. Cooper DN, Yousoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155

    Article  PubMed  CAS  Google Scholar 

  39. Refetoff S, Murata Y, Mori Y, Janssen OE, Takeda K, Hayashi Y (1996) Thyroxine-binding globulin: organization of the gene and variants. Horm Res 45:128–138

    Article  PubMed  CAS  Google Scholar 

  40. Tani Y, Mori Y, Miura Y, Okamoto H, Inagaki A, Saito H, Oiso Y (1994) Molecular cloning of the rat thyroxine-binding globulin gene and analysis of its promoter activity. Endocrinology 135:2731–2736

    Article  PubMed  CAS  Google Scholar 

  41. Irving JA, Pike RN, Lesk AM, Whisstock JC (2000) Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. Genome Res 10:1833–1835

    Article  Google Scholar 

  42. Pemberton PA, Stein PE, Pepys MB, Potter JM, Carrell RW (1988) Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336:257–258

    Article  PubMed  CAS  Google Scholar 

  43. Buettner C, Grasberger H, Hermansdorfer K, Chen B, Treske B, Janssen OE (1999) Characterization of the thyroxine-binding site of thyroxine-binding globulin by site-directed mutagenesis. Mol Endocrinol 13:1864–1872

    Article  PubMed  CAS  Google Scholar 

  44. Denecke J, De Rycke R, Botterman J (1992) Plant and mammalian sorting signals for protein retention in the endoplasmic reticulum contain a conserved epitope. EMBO J 11:2345–2355

    PubMed  CAS  Google Scholar 

  45. Ain KB, Mori Y, Refetoff S (1987) Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: a mechanism for estrogen induced elevation of serum TBG concentration. J Clin Endocrinol Metab 65:689–696

    Article  PubMed  CAS  Google Scholar 

  46. Den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12

    Article  Google Scholar 

Download references

Acknowledgement

This work was supported in part by grants from MURST (Cofin 2002063919-004), MIUR (Rome, Italy) and the USA National Institutes of Health (DK15070 and RR00055).

Author information

Authors and Affiliations

  1. Institute of Endocrine Sciences, University of Milan, Pad. Granelli Via F. Sforza, 35, Milan, 20122, Italy

    Deborah Mannavola, Guia Vannucchi, Laura Fugazzola, Valentina Cirello, Irene Campi, Luca Persani & Paolo Beck-Peccoz

  2. Fondazione Policlinico Instituto di Ricovero e Cura a Carattere Scientifico di natura pubblica (IRCCS), Milan, Italy

    Deborah Mannavola, Guia Vannucchi, Laura Fugazzola, Valentina Cirello, Irene Campi & Paolo Beck-Peccoz

  3. Pediatric Division, Ospedale Regionale di Bolzano, Bolzano, Italy

    Giorgio Radetti

  4. Istituto Auxologico Italiano-IRCCS, Milan, Italy

    Luca Persani

  5. Departments of Medicine and Pediatrics and the Committee on Genetics, The University of Chicago, Chicago, USA

    Samuel Refetoff

Authors
  1. Deborah Mannavola
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guia Vannucchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Fugazzola
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valentina Cirello
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irene Campi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giorgio Radetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luca Persani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Samuel Refetoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paolo Beck-Peccoz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paolo Beck-Peccoz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mannavola, D., Vannucchi, G., Fugazzola, L. et al. TGB Deficiency: description of two novel mutations associated with complete TBG deficiency and review of the literature. J Mol Med 84, 864–871 (2006). https://doi.org/10.1007/s00109-006-0078-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-006-0078-9

Keywords

Search

Navigation