Abstract
The FOXE1 gene was screened for mutations in a cohort of 34 unrelated patients with congenital hypothyroidism, 14 of whom had thyroid dysgenesis and 18 were normal (the thyroid status for 2 patients was unknown). The entire coding region of the FOXE1 gene was PCR-amplified, then analyzed using single-stranded conformational polymorphism, followed by confirmation by direct DNA sequencing. DNA sequencing analysis revealed a heterozygous A>G transition at nucleotide position 394 in one of the patients. The nucleotide transition changed asparagine to aspartate at codon 132 in the highly conserved region of the forkhead DNA binding domain of the FOXE1 gene. This mutation was not detected in a total of 104 normal healthy individuals screened. The binding ability of the mutant FOXE1 protein to the human thyroperoxidase (TPO) promoter was slightly reduced compared with the wild-type FOXE1. The mutation also caused a 5% loss of TPO transcriptional activity.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aza-Blanc P, Di Lauro R, Santisteban P (1993) 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
Baris I, Arisoy AE, Smith A, Agostini M, Mitchell CS, Park SM, Halefoglu AM, Zengin E, Chatterjee VK, Battaloglu E (2006) A novel missense mutation in human ttf-2 (fkhl15) gene associated with congenital hypothyroidism but not athyreosis. J Clin Endocrinol Metab 91:4183–4187
Castanet M, Park SM, Smith A, Bost M, Leger J, Lyonnet S, Pelet A, Czernichow P, Chatterjee VK, Polak M (2002) A novel loss-of-function mutation in ttf-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. Hum Mol Genet 11:2051–2059
Chadwick BP, Obermayr F, Frischauf AM (1997) FKHL15, a new human member of the forkhead gene family located on chromosome 9q22. Genomics 41(3):390–396
Civitareale D, Lonigro R, Sinclair AJ, Di Lauro R (1989) A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. EMBO J 8:2537–2542
Clifton-Bligh RJ, Gregory JW, Ludgate M, John R, Persani L, Asteria C, Beck-Peccoz P, Chatterjee VK (1997) Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH. J Clin Endocrinol Metab 82:1094–1100
Clifton-Bligh RJ, Wentworth JM, Heinz P, Crisp MS, John R, Lazarus JH, Ludgate M, Chatterjee VK (1998) Mutation of the gene encoding human ttf-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet 19:399–401
Congdon T, Nguyen LQ, Nogueira CR, Habiby RL, Medeiros-Neto G, Kopp P (2001) A novel mutation (Q40P) in Pax8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child. J Clin Endocrinol Metab 86:3962–3967
Damante G, Di Lauro R (1994) Thyroid-specific gene expression. Biochim Biophys Acta 1218(3):255–266
de Roux N, Misrahi M, Brauner R, Houang M, Carel JC, Granier M, Le Bouc Y, Ghinea N, Boumedienne A, Toublanc JE, Milgrom E (1996) Four families with loss of function mutations of the thyrotropin receptor. J Clin Endocrinol Metab 81:4229–4235
Krude H, Schutz B, Biebermann H, Von Moers A, Schnabel D, Neitzel H, Tonnies H, Weise D, Lafferty A, Schwarz S, De Felice M, Von Deimling A, Van Landeghem F, Di Lauro R, Gruters A (2002) Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J Clin Invest 109(4):475–480
Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Battacharya SS (2003) FOX’s in development and disease. Trends Genet 19:339–344
Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Grüters A, Busslinger M, Di Lauro L (1998) PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 19(1):83–86
Meeus L, Gilbert B, Rydlewski C, Parma J, Roussie AL, Abramowicz M, Vilain C, Christophe D, Costagliola S, Vassart G (2004) Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. J Clin Endocrinol Metab 89:4285–4291
Musa M, Harun F, Junit SM (2007) Molecular analysis of the thyroid stimulating hormone receptor gene in unrelated patients with congenital hypothyroidism. Mal J Biochem Mol Biol 15:8–18
Ortiz L, Aza-Blanc P, Zannini M, Cato AC, Santisteban P (1999) The interaction between the forkhead thyroid transcription factor ttf-2 and the constitutive factor ctf/nf-1 is required for efficient hormonal regulation of the thyroperoxidase gene transcription. J Biol Chem 274:15213–15221
Park SM, Chatterjee VK (2005) Genetics of congenital hypothyroidism. J Med Genet 42:379–389
Pohlenz J, Dumitrescu A, Zundel D, Martine U, Schönberger W, Koo E, Weiss RE, Cohen RN, Kimura S, Refetoff S (2002) Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J Clin Invest 109:469–473
Santisteban P, Acebron A, Polycarpou-Schwarz M, Di Lauro R (1992) Insulin and insulin-like growth factor I regulate a thyroid-specific nuclear protein that binds to the thyroglobulin promoter. Mol Endocrinol 6:1310–1317
Toublanc JE (1992) Comparison of epidemiological data on congenital hypothyroidism in Europe with those of other parts in the world. Horm Res 38(5–6):230–235
Toublanc JE (2002) Hypothyroidism in the child. Rev Prat 52:1115–1118
Vilain C, Rydlewski C, Duprez L, Heinrichs C, Abramowicz M, Malvaux P, Renneboog B, Parma J, Costagliola S, Vassart G (2001) Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of Pax8. J Clin Endocrinol Metab 86:234–238
Watkins WJ, Harris SE, Craven MJ, Vincent AL, Winship IM, Gersak K, Shelling AN (2006) An investigation into foxe1 polyalanine tract length in premature ovarian failure. Mol Hum Reprod 12:145–149
Yong PH, Harun F, Junit SM (2007) Molecular analysis of PAX8 gene in unrelated patients with congenital hypothyroidism. Internet J Endocrinol 3(2)
Zannini M, Avantaggiato V, Biffali E, Arnone MI, Sato K, Pischetola M, Taylor BA, Phillips SJ, Simeone A, Di Lauro R (1997) 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
Acknowledgments
This research was funded by grants FP005/2003C (Fundamental grant) from the University of Malaya, FP070/2007 (FRGS) from the Ministry of Higher Education, Malaysia, and 12-02-03-2061 (Science fund) from the Ministry of Science, Technology, and Innovation, Malaysia.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kang, IN., Musa, M., Harun, F. et al. Characterization of Mutations in the FOXE1 Gene in a Cohort of Unrelated Malaysian Patients with Congenital Hypothyroidism and Thyroid Dysgenesis. Biochem Genet 48, 141–151 (2010). https://doi.org/10.1007/s10528-009-9306-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10528-009-9306-7