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NKX2-1 gene
URL of this page: https://medlineplus.gov/genetics/gene/nkx2-1/

NKX2-1 gene

NK2 homeobox 1

Normal Function

The NKX2-1 gene provides instructions for making a protein called homeobox protein Nkx-2.1, which is a member of the homeobox protein family. Homeobox proteins direct the formation of body structures during early embryonic development. Homeobox protein Nkx-2.1 is particularly involved in the development and function of the brain, lungs, and thyroid gland. The thyroid is a butterfly shaped gland in the lower neck that makes hormones to help regulate a wide variety of critical body functions, including growth and brain development.

Homeobox protein Nkx-2.1 functions as a transcription factor, which means it attaches to DNA and controls the activity (expression) of other genes. In the brain, homeobox protein Nkx-2.1 regulates genes that play a role in the development and movement (migration) of specialized nerve cells (neurons), called interneurons, to their proper location. Interneurons relay signals between other neurons. In the lungs, homeobox protein Nkx-2.1 controls development of lung structures and regulates the expression of surfactant genes, which provide instructions for producing surfactant proteins. Together with certain fats, these proteins form surfactant, which lines the lung tissue and makes breathing easy. In the thyroid gland, homeobox protein Nkx-2.1 controls genes that are critical in the production of thyroid hormones.

Health Conditions Related to Genetic Changes

Brain-lung-thyroid syndrome

At least 100 mutations in the NKX2-1 gene have been found to cause brain-lung-thyroid syndrome, which encompasses a group of conditions that affect the brain, lungs, and thyroid gland. About half of affected individuals have problems with all three organs, while others have problems with one or two of them. The most common features of this syndrome are benign hereditary chorea, which involves involuntary jerking movements (chorea) of the face, torso, and limbs and other uncontrolled movements; severe breathing difficulty (respiratory distress syndrome); and reduced thyroid gland function (hypothyroidism).

Many of the NKX2-1 gene mutations involved in brain-lung-thyroid syndrome result in an abnormally short homeobox protein Nkx-2.1 that cannot function normally. Other mutations change single protein building blocks (amino acids) in the protein, impairing its ability to attach to DNA. Still others delete the whole NKX2-1 gene. A shortage of functional homeobox protein Nkx-2.1 alters the expression of genes important for the normal development and functioning of the brain, lungs, and thyroid. The production of surfactant proteins is reduced, leading to breathing difficulty; expression of genes involved in the production of thyroid hormones is impaired, accounting for hypothyroidism; and brain development is impaired, likely due to improper interneuron formation or migration, which may underlie the movement abnormalities characteristic of brain-lung-thyroid syndrome.

More About This Health Condition

Other Names for This Gene

  • BCH
  • BHC
  • homeobox protein NK-2 homolog A
  • homeobox protein Nkx-2.1 isoform 1
  • homeobox protein Nkx-2.1 isoform 2
  • NK-2
  • NK-2 homolog A
  • NKX2.1
  • NKX2A
  • NMTC1
  • T/EBP
  • TEBP
  • thyroid nuclear factor 1
  • thyroid transcription factor 1
  • thyroid-specific enhancer-binding protein
  • TITF1
  • TTF-1
  • TTF1

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Butt SJ, Sousa VH, Fuccillo MV, Hjerling-Leffler J, Miyoshi G, Kimura S, Fishell G. The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron. 2008 Sep 11;59(5):722-32. doi: 10.1016/j.neuron.2008.07.031. Citation on PubMed or Free article on PubMed Central
  • Carre A, Szinnai G, Castanet M, Sura-Trueba S, Tron E, Broutin-L'Hermite I, Barat P, Goizet C, Lacombe D, Moutard ML, Raybaud C, Raynaud-Ravni C, Romana S, Ythier H, Leger J, Polak M. Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case. Hum Mol Genet. 2009 Jun 15;18(12):2266-76. doi: 10.1093/hmg/ddp162. Epub 2009 Mar 31. Citation on PubMed
  • Guillot L, Carre A, Szinnai G, Castanet M, Tron E, Jaubert F, Broutin I, Counil F, Feldmann D, Clement A, Polak M, Epaud R. NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in "Brain-Lung-Thyroid Syndrome". Hum Mutat. 2010 Feb;31(2):E1146-62. doi: 10.1002/humu.21183. Citation on PubMed
  • 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. 2002 Feb;109(4):475-80. doi: 10.1172/JCI14341. Citation on PubMed or Free article on PubMed Central
  • Nettore IC, Mirra P, Ferrara AM, Sibilio A, Pagliara V, Kay CS, Lorenzoni PJ, Werneck LC, Bruck I, Dos Santos LH, Beguinot F, Salvatore D, Ungaro P, Fenzi G, Scola RH, Macchia PE. Identification and functional characterization of a novel mutation in the NKX2-1 gene: comparison with the data in the literature. Thyroid. 2013 Jun;23(6):675-82. doi: 10.1089/thy.2012.0267. Citation on PubMed
  • Nobrega-Pereira S, Kessaris N, Du T, Kimura S, Anderson SA, Marin O. Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors. Neuron. 2008 Sep 11;59(5):733-45. doi: 10.1016/j.neuron.2008.07.024. Citation on PubMed or Free article on PubMed Central
  • Shetty VB, Kiraly-Borri C, Lamont P, Bikker H, Choong CS. NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients. J Pediatr Endocrinol Metab. 2014 Mar;27(3-4):373-8. doi: 10.1515/jpem-2013-0109. Citation on PubMed
  • Williamson S, Kirkpatrick M, Greene S, Goudie D. A novel mutation of NKX2-1 affecting 2 generations with hypothyroidism and choreoathetosis: part of the spectrum of brain-thyroid-lung syndrome. J Child Neurol. 2014 May;29(5):666-9. doi: 10.1177/0883073813518243. Epub 2014 Jan 21. Citation on PubMed

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