NKX2-1
MIM.600635 14q13.3 HGNC:11825
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Definition: Thyroid transcription factor-1 (TTF-1) is a 38-kd homeodomain containing DNA-binding protein originally identified in follicular cells of the thyroid and subsequently in pneumocytes. TTF-1 is one of the three most important transcription factors for thyroid gland organogenesis.
Expression in normal cells
follicular cells of the thyroid
Expression in tumors
pulmonary small cell carcinomas (82.7%)
extrapulmonary small cell carcinomas (42.0%)
Pathology
germline mutations of TITF1 in
- benign hereditary chorea (MIM.118700)
- choreoathetosis and hypothyroidism (#16507635#)
- choreoathetosis, hypothyroidism and respiratory distress (MIM.118700)
- congenital alveolar proteinosis
- congenital hypothyroidism and benign chorea without pulmonary distress (#16507635#)
Immunochemistry
TTF-1 is one of the most commonly used markers in diagnostic pathology. It has shown a very high sensitivity and specificity in the diagnosis of tumors of pulmonary and thyroid lineage.
Immunostaining for thyroid transcription factor-1 (TTF-1) is frequently used to help assess the site of origin of metastatic carcinomas. TTF-1 expression is most frequently seen in carcinomas of thyroid and lung origin.
Expression varied from focal and weak to diffuse and strong and was seen in both invasive and in situ components. A small proportion of breast carcinomas show TTF-1 expression.
The presence of TTF-1 immunoreactivity in a carcinoma cannot by itself be used to exclude the possibility of a breast origin.
Pathology
TTF1-associated benign hereditary chorea (MIM.118700)
TTF1-associated choreoathetosis, hypothyroidism, and respiratory distress (MIM.610978)
TTF1-associated neonatal respiratory distress (MIM.610978)
- TTF1-associated infantile pneumopathy
References
TTF-1 in Embryonal Tumors: An Immunohistochemical Study of 117 Cases. Galliani CA, Bisceglia M, Lastilla G, Parafioriti A, Vita G, Rosai J. Am J Surg Pathol. 2011 Sep;35(9):1422-5. PMID: #21836486#
Lau SK, Luthringer DJ, Eisen RN. Thyroid transcription factor-1: a review. Appl Immunohistochem Mol Morphol. 2002 Jun;10(2):97-102. PMID: #12051643#
Thyroid transcription factor-1 expression in breast carcinomas. Robens J, Goldstein L, Gown AM, Schnitt SJ. Am J Surg Pathol. 2010 Dec;34(12):1881-5. PMID: #21107096#
DeFelice M, Silberschmidt D, DiLauro R, Xu Y, Wert SE, Weaver TE, Bachurski CJ, Clark JC, Whitsett JA. TTF-1 phosphorylation is required for peripheral lung morphogenesis, perinatal survival, and tissue-specific gene expression. J Biol Chem. 2003 Sep 12;278(37):35574-83. PMID: #12829717#
Acebron, A.; Aza-Blanc, P.; Rossi, D. L.; Lamas, L.; Santisteban, P. :
Congenital human thyroglobulin defect due to low expression of the thyroid-specific transcription factor TTF-1. J. Clin. Invest. 96: 781-785, 1995. PubMed ID : #7635972#
Asmus, F.; Horber, V.; Pohlenz, J.; Schwabe, D.; Zimprich, A.; Munz, M.; Schoning, M.; Gasser, T. : A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa. Neurology 64: 1952-1954, 2005. PubMed ID : #15955952#
Breedveld, G. J.; van Dongen, J. W. F.; Danesino, C.; Guala, A.; Percy, A. K.; Dure, L. S.; Harper, P.; Lazarou, L. P.; van der Linde, H.; Joosse, M.; Gruters, A.; MacDonald, M. E.; de Vries, B. B. A.; Arts, W. F. M.; Oostra, B. A.; Krude, H.; Heutink, P. : Mutations in TITF-1 are associated with benign hereditary chorea. Hum. Molec. Genet. 11: 971-979, 2002. PubMed ID : #11971878#
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. (Letter) New Eng. J. Med. 338: 1317-1318, 1998. PubMed ID : #9565498#
do Carmo Costa, M.; Costa, C.; Silva, A. P.; Evangelista, P.; Santos, L.; Ferro, A.; Sequeiros, J.; Maciel, P. : Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics 6: 209-215, 2005. PubMed ID : #16220345#
Doyle, D. A.; Gonzalez, I.; Thomas, B.; Scavina, M. :
Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1. J. Pediat. 145: 190-193, 2004. PubMed ID : #15289765#
Garcia-Barcelo, M.-M.; Lau, D. K.; Ngan, E. S.; Leon, T. Y.; Liu, T.; So, M.; Miao, X.; Lui, V. C.; Wong, K. K.; Ganster, R. W.; Cass, D. T.; Croaker, G. D. H.; Tam, P. K. : Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung’s disease locus. Ann. Hum. Genet. 71: 746-754, 2007. PubMed ID : #17640327#
Iwatani, N.; Mabe, H.; Devriendt, K.; Kodama, M.; Miike, T. :
Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. J. Pediat. 137: 272-276, 2000. PubMed ID : #10931427#
Kimura, S.; Hara, Y.; Pineau, T.; Fernandez-Salguero, P.; Fox, C. H.; Ward, J. M.; Gonzalez, F. J. : 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. PubMed ID : #8557195#
Krude, H.; Schutz, B.; Biebermann, H.; von Moers, A.; Schnabel, D.; Neitzel, H.; Tonnies, H.; Weise, D.; Lafferty, A.; Schwarz, S.; DeFelice, M.; von Deimling, A.; van Landeghem, F.; DiLauro, R.; Gruters, A. :
Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. J. Clin. Invest. 109: 475-480, 2002. PubMed ID : #11854319#
Pohlenz, J.; Dumitrescu, A.; Zundel, D.; Martine, U.; Schonberger, W.; Koo, E.; Weiss, R. E.; Cohen, R. N.; Kimura, S.; Refetoff, S. :
Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J. Clin. Invest. 109: 469-473, 2002. PubMed ID : #11854318#
Seidman, J. G.; Seidman, C. : Transcription factor haploinsufficiency: when half a loaf is not enough. (Commentary) J. Clin. Invest. 109: 451-455, 2002. PubMed ID : #11854316#
Trueba, S. S.; Auge, J.; Mattei, G.; Etchevers, H.; Martinovic, J.; Czernichow, P.; Vekemans, M.; Polak, M.; Attie-Bitach, T. : PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations. J. Clin. Endocr. Metab. 90: 455-462, 2005. PubMed ID : #15494458#
Weir, B. A.; Woo, M. S.; Getz, G.; Perner, S.; Ding, L.; Beroukhim, R.; Lin, W. M.; Province, M. A.; Kraja, A.; Johnson, L. A.; Shah, K.; Sato, M.; and 58 others : Characterizing the cancer genome in lung adenocarcinoma. Nature 450: 893-898, 2007. PubMed ID : #17982442#
Zhu, N. L.; Li, C.; Xiao, J.; Minoo, P. : NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells. Gene 327: 25-36, 2004. PubMed ID : #14960358#