Human Molecular Genetics, 2002, Vol. 11, No. 17 2051-2059
© 2002 Oxford University Press
A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate
1Paediatric Endocrinology Unit and INSERM U457, Paris, France, 2Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK, 3Department of Pediatrics, CHU, Grenoble and 4INSERM U393, Paris, France
Received May 22, 2002; Accepted June 24, 2002
Thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH) and its genetic basis is largely unknown. Here, we describe the second homozygous missense mutation in TTF-2 (or FOXE1), a transcription factor that has been implicated in thyroid development. Two male siblings, born to consanguineous parents, presented with CH, athyreosis and cleft palate and were found to be homozygous for a mutation corresponding to a serine to asparagine substitution at codon 57 (S57N) in the forkhead DNA binding domain of TTF-2. Their heterozygous parents were unaffected and this mutation was not found in 31 unrelated cases of athyreosis or normal controls. Consistent with its location, the S57N TTF-2 mutant protein showed impaired DNA binding and partial loss of transcriptional function. Such incomplete loss of TTF-2 function may account for the absence of choanal atresia and bifid epiglottis in our patients, anomalies which were present together with CH and cleft palate in two other individuals with the only other, more deleterious, TTF-2 mutation (A65V) described previously. Our observations support the role of TTF-2 in both thyroid and palate development but suggest phenotypic heterogeneity of this syndromic form of CH.
* To whom correspondence should be addressed at: Paediatric Endocrinology Unit and INSERM U 457, Hospital Robert Debré, 48 Bd Serurier, 75019 PARIS. Tel: 33 140032143; Fax: 33 140032429; Email: michel.polak{at}rdb.ap-hop-paris.fr
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  I. Cuesta, K. S. Zaret, and P. Santisteban The Forkhead Factor FoxE1 Binds to the Thyroperoxidase Promoter during Thyroid Cell Differentiation and Modifies Compacted Chromatin Structure Mol. Cell. Biol., October 15, 2007; 27(20): 7302 - 7314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Al Taji, H. Biebermann, Z. Limanova, O. Hnikova, J. Zikmund, C. Dame, A. Gruters, J. Lebl, and H. Krude Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism Eur. J. Endocrinol., May 1, 2007; 156(5): 521 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Baris, A. E. Arisoy, A. Smith, M. Agostini, C. S. Mitchell, S. M. Park, A. M. Halefoglu, E. Zengin, V. K. Chatterjee, and E. Battaloglu A Novel Missense Mutation in Human TTF-2 (FKHL15) Gene Associated with Congenital Hypothyroidism But Not Athyreosis J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4183 - 4187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Alt, O. A. Elsalini, P. Schrumpf, N. Haufs, N. D. Lawson, G. C. Schwabe, S. Mundlos, A. Gruters, H. Krude, and K. B. Rohr Arteries define the position of the thyroid gland during its developmental relocalisation. Development, October 1, 2006; 133(19): 3797 - 3804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Moya, G. Perez de Nanclares, L. Castano, N. Potau, J. R. Bilbao, A. Carrascosa, M. Bargada, R. Coya, P. Martul, E. Vicens-Calvet, et al. Functional Study of a Novel Single Deletion in the TITF1/NKX2.1 Homeobox Gene That Produces Congenital Hypothyroidism and Benign Chorea But Not Pulmonary Distress J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1832 - 1841. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Amendola, P. De Luca, P. E. Macchia, D. Terracciano, A. Rosica, G. Chiappetta, S. Kimura, A. Mansouri, A. Affuso, C. Arra, et al. A Mouse Model Demonstrates a Multigenic Origin of Congenital Hypothyroidism Endocrinology, December 1, 2005; 146(12): 5038 - 5047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bille, J. F. Winther, A. Bautz, J. C. Murray, J. Olsen, and K. Christensen Cancer Risk in Persons with Oral Cleft--A Population-based Study of 8,093 Cases Am. J. Epidemiol., June 1, 2005; 161(11): 1047 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S M Park and V K K Chatterjee Genetics of congenital hypothyroidism J. Med. Genet., May 1, 2005; 42(5): 379 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Trueba, J. Auge, G. Mattei, H. Etchevers, J. Martinovic, P. Czernichow, M. Vekemans, M. Polak, and T. Attie-Bitach PAX8, TITF1, and FOXE1 Gene Expression Patterns during Human Development: New Insights into Human Thyroid Development and Thyroid Dysgenesis-Associated Malformations J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 455 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Brancaccio, A. Minichiello, M. Grachtchouk, D. Antonini, H. Sheng, R. Parlato, N. Dathan, A. A. Dlugosz, and C. Missero Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis Hum. Mol. Genet., November 1, 2004; 13(21): 2595 - 2606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. De Felice and R. Di Lauro Thyroid Development and Its Disorders: Genetics and Molecular Mechanisms Endocr. Rev., October 1, 2004; 25(5): 722 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Meeus, B. Gilbert, C. Rydlewski, J. Parma, A. L. Roussie, M. Abramowicz, C. Vilain, D. Christophe, S. Costagliola, and G. Vassart 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., September 1, 2004; 89(9): 4285 - 4291. [Abstract] [Full Text] [PDF]
|
|