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.
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References
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).
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).
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).
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).
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).
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).
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).
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).
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).
Kaufmann, E. & Knöchel, W. Five years on the wings of forkhead. Mech. Dev. 57, 3– 20 (1996).
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).
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).
De Felice, M. et al. A mouse model for hereditary thyroid dysgenesis and cleft palate. Nature Genet. *, *-* ( 1998).
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).
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).
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).
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).
Mansouri, A., Chowdhury, K. & Gruss, P. Follicular cells of the thyroid gland require Pax8 gene function. Nature Genet. 19, 87–90 (1998).
Macchia, P.E. et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nature Genet. 19, 83–86 (1998).
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).
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).
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).
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).
Lazarus, J.H. & Hughes, I.A. Congenital abnormalities and congenital hypothyroidism. Lancet 2, 52 ( 1988).
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).
Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 ( 1987).
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).
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).
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).
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.).
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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
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DOI: https://doi.org/10.1038/1294
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