Alternative titles; symbols
HGNC Approved Gene Symbol: NKX2-1
SNOMEDCT: 230306001;
Cytogenetic location: 14q13.3 Genomic coordinates (GRCh38): 14:36,516,397-36,520,232 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q13.3 | {Thyroid cancer, nonmedullary, 1} | 188550 | Autosomal dominant | 3 |
| Chorea, hereditary benign | 118700 | Autosomal dominant | 3 | |
| Choreoathetosis, hypothyroidism, and neonatal respiratory distress | 610978 | Autosomal dominant | 3 |
The NKX2-1 gene encodes a transcription factor that is expressed during early development of thyroid, lung, and forebrain regions, particularly the basal ganglia and hypothalamus (summary by Thorwarth et al., 2014).
The protein referred to as thyroid transcription factor-1 (TTF1) by Guazzi et al. (1990) is a 38-kD nuclear protein that mediates thyroid-specific gene transcription. Guazzi et al. (1990) purified the protein from calf thyroids, obtained partial amino acid sequence and cloned the cDNA from a calf thyroid cDNA library using degenerate primers based on the peptide data. The human gene was obtained by Ikeda et al. (1995) and contains a homeobox domain and a 17-amino acid motif characteristic of the NKX2 family of transcription factors. TTF1 activates thyroglobulin (TG; 188450) and thyroperoxidase (TPO; 606765) gene transcription in thyroid adenocarcinomas and is expressed in epithelial cells of the rat thyroid. TTF1 also activates transcription of human surfactant protein B (SFTPB; 178640) in the lung.
Ikeda et al. (1995) screened a human genomic DNA cosmid library with the rat TTF1 cDNA. A subclone from the cosmid containing the gene was obtained and sequenced. The predicted 371-amino acid protein is 98% identical to the rat sequence. The predominant 2.4-kb RNA was shown to be expressed in pulmonary adenocarcinoma cells in addition to thyroid gland epithelium and the lung. TTF1 protein was detected in fetal lung as early as the eleventh week of gestation and localized in the nuclei of epithelial cells of the developing airways. After birth, expression was seen in type II epithelial cells in the alveoli and in some bronchiolar epithelial cells. When the 5-prime flanking region of the gene was placed in front of a luciferase reporter construct, activity could be measured in pulmonary adenocarcinoma cells.
Hamdan et al. (1998) isolated several NKX2.1 cDNAs from human lung, which they grouped into 4 distinct classes. All the cDNAs but one encode a protein identical to that reported by Ikeda et al. (1995). The remaining cDNA encodes a putative 402-amino acid protein with an N-terminal extension. Cell-free translation of a transcript encoding the longer protein resulted in polypeptides with apparent molecular masses of 44, 40, and 38 kD by SDS-PAGE. Translation of a transcript encoding the shorter protein resulted in polypeptides of 40 and 38 kD. Hamdan et al. (1998) hypothesized that the different polypeptides result from the use of alternate ATG codons.
Holland et al. (2007) stated that the NKX2-1 and NKX2-4 (607808) genes are collectively orthologous to Drosophila scro and comprise the Nk2.1 gene family.
Both TTF1 and PAX8 (167415) are thyroid-specific transcription factors that preferentially bind to the thyroglobulin and thyroperoxidase promoters, respectively (Acebron et al., 1995).
Using yeast 2-hybrid analysis, Yang et al. (2001) showed that BR22 (CCDC59; 619280) interacted with TTF1, and in vitro binding assays with purified recombinant proteins confirmed direct interaction. BR22 and TTF1 formed a complex in transfected HEK293 cells and acted synergistically to increase transactivation activity of the human surfactant protein B (SPB, or SFTPB; 178640) promoter.
Using immunoprecipitation analysis, Yang et al. (2003) showed that endogenous TAP26 and TTF1 interacted and formed a complex in H441 human lung epithelial cells.
Using chromatin immunoprecipitation analysis, Yang et al. (2006) identified TAP26 as a coactivator with TTF1 on both the SPB and SPC (SFTPC; 178620) promoter complexes. The TTF1/TAP26 complex stimulated both SPB and SPC promoter activities in H441 cells in a dose-dependent manner. TAP26 alone induced SPB promoter activity, but not SPC promoter activity, in H441 cells. However, in mouse lung MLE12 cells, the TTF1/TAP26 complex or TAP26 alone stimulated only SPB promoter activity, but not SPC promoter activity. The findings indicated that the mechanism for response of the SPC promoter to the complex was different from that of the SPB promoter, and that neither TTF1 nor TAP26 was the limiting factor for the SPC promoter in MLE12 cells. RT-PCR analysis showed that expression of TTF1 and TAP26 was lower in H441 cells compared with MLE12 cells, suggesting that TTF1/TAP26 complex-activated SPC promoter activity was already optimized in MLE12 cells, but not in H441 cells. In addition, SPC promoter stimulation by the TTF1/TAP26 complex in MLE12 cells required TTF1-binding sites T4 and T5 in the proximal region of the SPC promoter.
Zhu et al. (2004) presented evidence that mouse Titf1, which they called Nkx2.1, is a potential upstream regulator of Bmp4 (112262) expression in lung. Titf1 and Bmp4 were coexpressed in developing mouse lungs. Using EMSA and cotransfection assays in mammalian lung epithelial cells, Zhu et al. (2004) identified functional cis-active Titf1 response elements in both Bmp4 promoter regions.
Dentice et al. (2005) determined that Titf1 directly controls expression of the pendrin gene (SLC26A4; 605646) in rat thyroid.
To gain insight into human thyroid development and thyroid dysgenesis-associated malformations, Trueba et al. (2005) studied the expression patterns of the PAX8, TITF1, and FOXE1 (602617) genes during human development. PAX8 and TITF1 were first expressed in the median thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. The expression patterns of these genes in human show some differences from those reported in the mouse; Pax8, Titf1, and Foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor. The authors concluded that the expression patterns of these 3 genes correlate well with the phenotypes observed in patients carrying mutations of the corresponding gene.
Garcia-Barcelo et al. (2005) localized TITF1 to the myenteric and submucosa plexuses in adult human colon and to the mesenchyme of embryonic stomach, where it colocalized with RET (164761). Expression of TITF1 activated RET transcription via a predicted TITF1-binding site in the RET promoter region.
Weir et al. (2007) reported a large-scale project to characterize copy number alterations in primary lung adenocarcinomas. By analysis of 371 tumors using dense single-nucleotide polymorphism arrays, Weir et al. (2007) identified 57 significantly recurrent events. Weir et al. (2007) found that 26 of 39 autosomal chromosome arms showed consistent large-scale copy number gain or loss, of which only a handful had been linked to a specific gene. They also identified 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only 6 of these focal events were associated with mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, was found in about 12% of samples. On the basis of genomic and functional analyses, Weir et al. (2007) identified NKX2-1, which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate protooncogene involved in a significant fraction of lung adenocarcinomas.
Taniguchi et al. (2013) followed the development trajectory of chandelier cells, the most distinct interneurons that innervate the axon initial segment of pyramidal neurons and control action potential initiation. Chandelier cells mainly derive from the ventral germinal zone of the lateral ventricle during late gestation and require the homeodomain protein Nkx2.1 for their specification. They migrate with stereotyped routes, and schedule and achieve specific laminar distribution in the cortex. Taniguchi et al. (2013) concluded that the developmental specification of this bona fide interneuron type likely contributes to the assembly of a cortical circuit motif.
By genomic sequence analysis, Ikeda et al. (1995) determined that the TITF1 gene spans approximately 3.3 kb and contains 2 exons.
Hamdan et al. (1998) determined that the TITF1 gene contains 3 exons. They identified 2 regions that mediate basal promoter activity in lung epithelial cells, one within the first intron, and the other 5-prime to the first exon.
Guazzi et al. (1990) mapped the TITF1 gene by in situ hybridization to mouse chromosome 12C1-C3 and in humans to chromosome 14q12-q21 with most of the grains localized to 14q13.
Winslow et al. (2011) modeled human lung adenocarcinoma, which frequently harbors activating point mutations in KRAS (190070) and inactivation of the p53 (191170) pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumors are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed Winslow et al. (2011) to distinguish metastatic from nonmetastatic tumors and determine the gene expression alterations that distinguish these tumor types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumors. Gain- and loss-of-function experiments in cells derived from metastatic and nonmetastatic tumors demonstrated that Nkx2-1 controls tumor differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumors at defined developmental stages, and functional complementation experiments indicated that Nkx2-1 constrains tumors in part by repressing the embryonically restricted chromatin regulator Hmga2 (600698). Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas had focused attention on its oncogenic function, Winslow et al. (2011) stated that their data specifically linked Nkx2-1 downregulation to loss of differentiation, enhanced tumor seeding ability, and increased metastatic proclivity. Winslow et al. (2011) concluded that the oncogenic and suppressive functions of Nkx2-1 in the same tumor type substantiate its role as a dual function lineage factor.
Acebron et al. (1995) reported 3 sibs, a woman and 2 men, with congenital hypothyroid goiter due to defective thyroglobulin synthesis. In the sister, Northern blot analysis, RT-PCR, and electrophoretic mobility shift assays demonstrated virtual absence of TTF1 expression. She had normal levels of PAX8 mRNA and thyroperoxidase mRNA but very low levels of thyroglobulin mRNA. Acebron et al. (1995) stated that this was the first reported evidence of congenital goiter with thyroglobulin synthesis defect due to low expression of TTF1. The parents were unaffected and were not known to be related.
In 172 sporadic Chinese patients with Hirschsprung disease (HSCR; 142623), Garcia-Barcelo et al. (2005) identified HSCR-associated RET (164761) promoter SNPs that were highly correlated with disease. They determined that the promoter SNPs overlapped a predicted cis-acting TITF1-binding site. Functional analysis demonstrated that the HSCR-associated alleles decreased RET transcription. TITF1 expression activated transcription from the RET promoter, and TITF1-activated RET transcription was reduced by the HSCR-associated SNPs. The authors identified a Chinese patient with HSCR who was heterozygous for a gly322-to-ser (G322S) mutation in the TITF1 gene. The patient did not harbor a mutation in any of the known HSCR-associated genes. Mutant TITF1 specifically decreased the function of the TITF1 5E isoform when assessed on the HSCR-associated RET haplotype.
Garcia-Barcelo et al. (2007) analyzed the TITF1 gene in an additional 102 Chinese and 70 Australian Caucasian HSCR patients and identified a met3-to-leu (M3L) mutation in 2 of the Australian patients that was not found in 194 Chinese and 60 Caucasian unrelated controls. In vitro functional studies showed that M3L completely abolished the activation of RET by TITF1, irrespective of the HSCR-associated haplotype in the RET promoter.
Benign Hereditary Chorea
In affected members of a family with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) identified a heterozygous 1.2-Mb deletion including the TITF1 gene. The authors also reported other BHC families with heterozygous point mutations in the TITF1 gene (see, e.g., 600635.0001-600635.0004).
Choreoathetosis and Congenital Hypothyroidism with or without Pulmonary Dysfunction
Devriendt et al. (1998) identified deletion of the TTF1 gene in an infant with choreoathetosis and congenital hypothyroidism with pulmonary dysfunction (CAHTP; 610978). The infant presented with respiratory failure, hypotonia, and truncal ataxia. Iwatani et al. (2000) reported deletion of the gene in 2 sibs with hypothyroidism and respiratory failure.
In a 6-year-old boy with dyskinesia, neonatal respiratory distress, and compensated hypothyroidism, Pohlenz et al. (2002) found a heterozygous mutation in the TITF1 gene (600635.0010). Pohlenz et al. (2002) concluded that haploinsufficiency of the TITF1 gene results in a predominantly neurologic phenotype and secondary hyperthyrotropinemia.
In 5 unrelated patients with variable degrees of congenital hypothyroidism, choreoathetosis, muscular hypotonia, and pulmonary problems, Krude et al. (2002) identified 5 different heterozygous loss-of-function mutations in the TTF1 gene: 1 complete gene deletion, 1 missense mutation, and 3 nonsense mutations (see, e.g., 600635.0005 and 600635.0006). The association of symptoms in the patients with TTF1 mutations pointed to an important role of the human gene in the development and function of the thyroid, basal ganglia, and lung, as had previously been described in rodents (Kimura et al., 1996). In 1 of the patients, cytogenetic studies identified an interstitial deletion of chromosomal region 14q11.2-q13.3, including the TTF1 gene. Choreoathetosis and respiratory distress were severe, and pulmonary infections were frequent and severe. Thyroid gland imaging showed hypoplasia.
Seidman and Seidman (2002) commented on Pohlenz et al. (2002) and Krude et al. (2002) and noted that haploinsufficiency is often the mechanism by which transcription factor defects cause disease. They discussed the diversity of transcription factor haploinsufficiency disorders and tabulated 32 genes that encode transcription factors and cause disease through haploinsufficiency.
In 4 affected members of a German family with choreoathetosis, congenital hypothyroidism, and neonatal respiratory insufficiency, Asmus et al. (2005) identified a heterozygous mutation in the TITF1 gene (600635.0008). Two patients had a favorable response to levodopa treatment.
In a patient with choreoathetosis and congenital hypothyroidism, Carre et al. (2009) identified a de novo heterozygous pro202-to-leu (P202L) mutation in the homeodomain of the NKX2-1 gene. Functional analysis of the P202L mutation revealed loss of transactivation capacity on the human thyroglobulin (TG; 188450) enhancer/promoter. Deficient transcriptional activity of the P202L mutant was completely rescued by cotransfected PAX8 (167415), whereas the synergistic effect was abolished by 2 other missense mutations (L176V and Q210P).
Nonmedullary Thyroid Cancer
Ngan et al. (2009) identified 4 of 20 unrelated patients with multinodular goiter (MNG)/papillary thyroid carcinoma (PTC) (NMTC1; 188550) who had an ala339-to-val (A339V) mutation in the TITF1 gene (600635.0012). Three of the 4 patients had more advanced tumors than did the remaining 16 patients. Two of these 4 patients had a positive family history of PTC, and the A339V mutation segregated with the phenotype in these families. The mutation was not found among 349 healthy control subjects or among 284 PTC patients who had no history of MNG. Patients carrying the mutation had a higher incidence of perineural infiltration, but it was not statistically significant. Patients carrying the mutation were also more likely than those without the mutation to have had previous thyroid surgery (50% vs 4.0%, p less than 0.001) and MNG (100% vs 5.3%, p less than 0.001).
Kimura et al. (1996) used homologous recombination to generate mice lacking the Ttf1 gene, or T/ebp. Heterozygotes developed normally, but homozygous deficient mice were born dead and lacked lung parenchyma. The deficient mice lacked a thyroid gland but had a normal parathyroid. In the brain, multiple defects were found in the ventral region of the forebrain, and the entire pituitary was missing. In situ hybridization analysis showed that the T/ebp gene is expressed in normal thyroid, lung bronchial epithelium, and specific areas of the forebrain during early embryogenesis. Kimura et al. (1996) concluded that the TTF1 gene is essential in the embryonic differentiation of the thyroid, lung, ventral forebrain, and pituitary.
Pohlenz et al. (2002) found that Ttf1 +/- mice demonstrated poor coordination and increased serum thyrotropin.
In an Italian mother and daughter with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) discovered a 1.2-Mb deletion on chromosome 14q which included the TITF1 gene. Haplotype analysis revealed that the mutant chromosome was derived from the grandmother.
In a 4-generation Dutch family with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) reported heterozygosity for a 727C-A transversion in the TITF1 gene, which was predicted to result in an arg243-to-ser (R243S) substitution.
In a 4-generation American family with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) reported heterozygosity for a 713G-T transversion in the TITF1 gene, which was predicted to result in a trp238-to-leu (W238L) substitution.
In a 3-generation British family with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) reported heterozygosity for a 908G deletion in the TITF1 gene, which was predicted to result in a frameshift and termination of transcription at codon 380. Seventy-seven amino acids are altered, and the terminal 22 amino acids were predicted to be lacking from the mutant protein.
In a 15-year-old patient with choreoathetosis, hypothyroidism, and pulmonary dysfunction (CAHTP; 610978), Krude et al. (2002) identified a heterozygous 2626G-T transversion in exon 3 of the TITF1 gene, resulting in a val45-to-phe (V45F) substitution in a highly conserved residue within the DNA binding homeodomain of the protein. The patient had apparent athyreosis on neonatal scintigraphy; a hypoplastic thyroid gland was detected on later ultrasound.
In a 3-year-old boy with choreoathetosis and mild thyroid dysfunction (see 610978), Krude et al. (2002) identified a heterozygous 2-bp insertion (2595insGG) in exon 3 of the TITF1 gene, resulting in a frameshift that led to a truncated protein lacking the entire third helix of the homeodomain. The patient was affected predominantly by choreoathetosis and had only mild thyroid dysfunction with elevated thyroid-stimulating hormone (TSH) and normal serum thyroid hormone concentrations. The boy had no respiratory distress, and had had only a few mild pulmonary infections.
In affected members of a family segregating autosomal dominant benign hereditary chorea (BHC; 118700), Kleiner-Fisman et al. (2003) identified a heterozygous -2A-T change in the invariant AG splice acceptor site of intron 2 of the TITF1 gene. The mutation is predicted to lead to an aberrant transcript affecting the sequence of exon 3.
In 4 affected members of a family with autosomal dominant choreoathetosis, congenital hypothyroidism, and pulmonary dysfunction (CAHTP; 610978), Asmus et al. (2005) identified a heterozygous 523G-T transversion in exon 3 of the TITF1 gene, resulting in a glu175-to-ter (E175X) substitution. Two patients had a favorable response to levodopa treatment.
In a Portuguese mother and son with benign hereditary chorea (BHC; 118700), Costa et al. (2005) identified a heterozygous 745C-T transition in the TITF1 gene, resulting in a gln249-to-ter (Q249X) substitution at the end of helix III of the homeodomain. The mutation is predicted to yield a protein lacking its 153 C-terminal amino acids, including the entire NK2-specific domain. Brain MRI showed symmetrical foci of hyperintense signals in the basal ganglia of the mother and subtle abnormalities of the cerebellum in the son. Neither patient had evidence of thyroid dysfunction.
In a 6-year-old boy with dyskinesia, neonatal respiratory distress requiring mechanical ventilation, and compensated hypothyroidism (CAHTP; 610978), Pohlenz et al. (2002) identified a heterozygous 1-bp insertion (255insG) in the TITF1 gene (600635.0009), resulting in a nonsense protein of 407 amino acids, rather than the normal 371. The mutant TITF1 did not bind to its canonic cis element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TITF1. Failure of mutant TITF1 to interfere with binding and transactivation functions of wildtype TITF1 suggested that the syndrome was caused by haploinsufficiency.
In 4 affected members of a 3-generation family with autosomal dominant congenital hypothyroidism, neonatal respiratory distress, and choreoathetosis (CAHTP; 610978), Doyle et al. (2004) identified a heterozygous A-to-G transition (376-2A-G) in intron 2 of the TITF1 gene. The mutation was predicted to prevent splicing of exons 2 and 3, resulting in a truncated protein and haploinsufficiency of the gene product.
Carre et al. (2009) identified heterozygosity for the 376-2A-G mutation in monozygotic twins. The mutation occurred de novo. One twin showed neonatal respiratory distress, congenital hypothyroidism, developed chronic pulmonary infections, and was diagnosed with choreoathetosis at age 5 years. The other twin showed neonatal respiratory distress and congenital hypothyroidism but had no respiratory problems after the neonatal period and had no neurologic symptoms through age 16 years.
In 4 of 20 unrelated patients with multinodular goiter (MNG)/papillary thyroid carcinoma (PTC) (NMTC1; 188550), Ngan et al. (2009) identified a C-to-T transition at nucleotide 1016 of the TITF1 gene (1016C-T, NM_003317), resulting in an ala339-to-val (A339V) substitution. Two of these 4 patients had a positive family history of PTC. In the first family, 2 family members with the mutation had a history of MNG followed by PTC, whereas the other 2 sibs who carried the mutation had clinically palpable MNG but no evidence of PTC. In the second family, the proband had a history of MNG before PTC, and the other 2 mutation carriers had MNG. The mutation was not found in unaffected members of either family. The mutation was not found among 349 healthy control subjects or among 284 PTC patients who had no history of MNG. Overexpression of A339V mutant protein in PCCL3 cells was associated with increased cell proliferation compared to overexpression of wildtype, including thyrotropin (see 188540)-independent growth (average A339V proliferation rate = 134.27%, wildtype rate = 104.43%, difference = 34.3%, 95% confidence interval = 12.0-47.7%, p = 0.010). Enhanced STAT3 (102582) activation and impaired transcription of the thyroid-specific genes TG (188450), TSHR (603372), and PAX8 (167415) were also observed in response to overexpression of A339V mutant TITF1.
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