Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia

Abstract

Congenital hypothyroidism occurs in one of every three to four thousand newborns, owing to complete or partial failure of thyroid gland development1. Although thyroid hypoplasia has recently been associated with mutations in the thyrotropin (TSH) receptor2,3, the cause of thyroid agenesis is unknown. Proteins including thyroid transcription factors 1 (TTF-1; refs 4, 5) and 2 (TTF-2; refs 6, 7) and Pax8 (refs 8, 9) are abundant in the developing mouse thyroid and are known to regulate genes expressed during its differentiation (for example, thyroid peroxidase and thyroglobulin genes). TTF-2 is a member of the forkhead/winged-helix domain transcription factor family, many of which are key regulators of embryogenesis10. Here we report that the transcription factor FKHL15 (ref. 11) is the human homologue of mouse TTF-2 (encoded by the Titf2 gene) and that two siblings with thyroid agenesis, cleft palate and choanal atresia12 are homozygous for a missense mutation (Ala65Val) within its forkhead domain. The mutant protein exhibits impaired DNA binding and loss of transcriptional function. Our observations represent the first description of a genetic cause for thyroid agenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: FKHL15 is the human homologue of TTF-2.
Figure 2: A missense mutation in FKHL15.
Figure 3: DNA binding studies.
Figure 4: Transfection studies.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Grant, D.B. & Smith, I. Survey of neonatal screening for primary hypothyroidism in England, Wales, and Northern Ireland 1982-1984. B. M. J. 296, 1355–1358 (1988).

    Article  CAS  Google Scholar 

  2. Biebermann, H., Grüters, A., Schönenberg, T. & Gudermann, T. Congenital hypothyroidism caused by mutations in the thyrotropin-receptor gene. N. Engl. J. Med. 336, 1390– 1391 (1997).

    Article  CAS  Google Scholar 

  3. Abramowicz, M.J., Duprez, L., Parma, J., Vassart, G. & Heinrichs C. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J. Clin. Invest. 99, 3018– 3024 (1997).

    Article  CAS  Google Scholar 

  4. Guazzi, S. et al. Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J. 9, 3631 –3639 (1990).

    Article  CAS  Google Scholar 

  5. Mizuno, K., Gonzalez, F.J. & Kimura, S. Thyroid-specific enhancer-binding protein (T/EBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1. Mol. Cell. Biol. 11, 4927– 4933 (1991).

    Article  CAS  Google Scholar 

  6. Francis-Lang, H., Price, M., Polycarpou-Schwartz, M. & Di Lauro, R. Cell-type-specific expression of the rat thyroperoxidase promoter indicates common mechanisms for thyroid-specific gene expression. Mol. Cell. Biol. 12, 576–588 ( 1992).

    Article  CAS  Google Scholar 

  7. Zannini, M. et al. TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation . EMBO J. 16, 3185–3197 (1997).

    Article  CAS  Google Scholar 

  8. Zannini, M., Francis-Lang, H., Plachov, D. & Di Lauro, R. Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters. Mol. Cell. Biol. 12, 4230– 4241 (1992).

    Article  CAS  Google Scholar 

  9. Plachov, D. et al. Pax-8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development 110, 643–651 (1990).

    CAS  PubMed  Google Scholar 

  10. Kaufmann, E. & Knöchel, W. Five years on the wings of forkhead. Mech. Dev. 57, 3– 20 (1996).

    Article  CAS  Google Scholar 

  11. Chadwick, B.P., Obermayr, F. & Frischauf, A-M. FKHL15, a new human member of the forkhead gene family located on chromosome 9q22. Genomics 41 , 390–396 (1997).

    Article  CAS  Google Scholar 

  12. Bamforth, J.S., Hughes, I.A., Lazarus, J.H., Weaver, C.M. & Harper, P.S. Congenital hypothyroidism, spiky hair, and cleft palate. J. Med. Genet. 26, 49–51 (1989).

    Article  CAS  Google Scholar 

  13. De Felice, M. et al. A mouse model for hereditary thyroid dysgenesis and cleft palate. Nature Genet. *, *-* ( 1998).

    PubMed  Google Scholar 

  14. Aza-Blanc, P., Di Lauro, R. & Sanisteban, P. Identification of a cis-regulatory element and a thyroid-specific nuclear factor mediating the hormonal regulation of rat thyroid peroxidase promoter activity. Mol. Endocrinol. 7, 1297 –1306 (1993).

    CAS  PubMed  Google Scholar 

  15. Grant, D.B., Smith, I., Fuggle, P.W., Tokar, S. & Chapple, J. Congenital hypothyroidism detected by neonatal screening: relationship between biochemical severity and early clinical features. Arch. Dis. Child. 67, 87–90 (1992).

    Article  CAS  Google Scholar 

  16. Stein, S.A. et al. Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse. Mol Endocrinol. 8, 129–138 (1994).

    CAS  PubMed  Google Scholar 

  17. Ahlbom, B.E. et al. Genetic and linkage analysis of familial congenital hypothyroidism: exclusion of linkage to the TSH receptor gene. Hum. Genet. 99 , 186–190 (1997).

    Article  CAS  Google Scholar 

  18. Mansouri, A., Chowdhury, K. & Gruss, P. Follicular cells of the thyroid gland require Pax8 gene function. Nature Genet. 19, 87–90 (1998).

    Article  CAS  Google Scholar 

  19. Macchia, P.E. et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nature Genet. 19, 83–86 (1998).

    Article  CAS  Google Scholar 

  20. Kimura, S. et al. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary . Genes Dev 10, 60–69 (1996).

    Article  CAS  Google Scholar 

  21. Perna, M.G. et al. Absence of mutations in the gene encoding thyroid transcription factor-1 (TTF-1) in patients with thyroid dysgenesis. Thyroid 7, 377–381 (1997).

    Article  CAS  Google Scholar 

  22. Lapi, P. et al. Mutations in the gene encoding thyroid transcription factor-1 (TTF-1) are not a frequent cause of congenital hypothyroidism (CH) with thyroid dysgenesis . Thyroid 7, 383–387 (1997).

    Article  CAS  Google Scholar 

  23. Devriendt, K., Vanhole, C., Matthijs, G. & de Zegher, F. Deletion of Thyroid Transcription Factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N. Engl. J .Med. 338, 1317–1318 (1998).

    Article  CAS  Google Scholar 

  24. Lazarus, J.H. & Hughes, I.A. Congenital abnormalities and congenital hypothyroidism. Lancet 2, 52 ( 1988).

    Article  CAS  Google Scholar 

  25. Roberts, H.E., Moore, C.A., Fernhoff, P.M., Brown, A.L. & Khoury, M.J. Population study of congenital hypothyroidism and associated birth defects, Atlanta, 1979-1992. Am. J. Med. Genet. 71, 29–32 ( 1997).

    Article  CAS  Google Scholar 

  26. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 ( 1987).

    Article  CAS  Google Scholar 

  27. Samuels, H.H., Tsai, J.S., Casanova, J. & Stanley, F. Thyroid hormone action: in vitro characterisation of solubilised nuclear receptors from rat liver and cultured GH1 cells. J. Clin. Invest. 54, 853–865 (1974).

    Article  CAS  Google Scholar 

  28. Wood, W.M., Kao, M.Y., Gordon, D.F. & Ridgeway, E.C. Thyroid hormone regulates mouse thyrotropin b-subunit gene promoter in transfected primary thyrotropes. J. Biol. Chem. 264, 14840–14847 (1989).

    CAS  PubMed  Google Scholar 

  29. Adams, M. et al. Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone: identification of thirteen novel mutations in the thyroid hormone receptor b gene. J. Clin. Invest. 94, 506–515 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Ferguson-Smith for the gift of the cosmid containing the FKHL15 genomic clone and D. Halsall for help in preparing this manuscript. R.C.-B. is a Commonwealth Scholar, J.W. is supported by an Elmore Studentship. This work was supported by the Wellcome Trust (V.K.K.C.) and the Medical Research Council (M.L.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. Krishna Chatterjee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clifton-Bligh, R., Wentworth, J., Heinz, P. et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 19, 399–401 (1998). https://doi.org/10.1038/1294

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/1294

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing