Genomes and Genes
Gene Symbol: NKX2 5
Description: NK2 homeobox 5
Alias: CHNG5, CSX, CSX1, HLHS2, NKX2.5, NKX2E, NKX4-1, VSD3, homeobox protein Nkx-2.5, NK2 transcription factor related, locus 5, NKX 2-5, cardiac-specific homeobox 1, homeobox protein CSX, homeobox protein NK-2 homolog E, homeobox protein NKX 2-5, tinman paralog
Products: NKX2 5
- Dentice M, Cordeddu V, Rosica A, Ferrara A, Santarpia L, Salvatore D, et al. Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocrinol Metab. 2006;91:1428-33 pubmed..Our results suggest a previously unknown role of NKX2-5 in the pathogenesis of TD. ..
- Brewer A, Alexandrovich A, Mjaatvedt C, Shah A, Patient R, Pizzey J. GATA factors lie upstream of Nkx 2.5 in the transcriptional regulatory cascade that effects cardiogenesis. Stem Cells Dev. 2005;14:425-39 pubmed
- Peng T, Wang L, Zhou S, Li X. Mutations of the GATA4 and NKX2.5 genes in Chinese pediatric patients with non-familial congenital heart disease. Genetica. 2010;138:1231-40 pubmed publisher..This study suggests that GATA4 and NKX2.5 missense mutations may be associated with congenital heart defects in pediatric Chinese patients. Further clinical studies with large samples are warranted. ..
- Reamon Buettner S, Borlak J. NKX2-5: an update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD). Hum Mutat. 2010;31:1185-94 pubmed publisher..Here, we summarize published NKX2-5 germline mutations and explore different avenues in disease pathogenesis to support the notion of a multifactorial cause of CHD where possibly several genes and associated pathways are involved. ..
- Narumi S, Muroya K, Asakura Y, Adachi M, Hasegawa T. Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients. J Clin Endocrinol Metab. 2010;95:1981-5 pubmed publisher..Using a population-based sample, we confirmed that a minor subset of CH patients has transcription factor mutations, but they are rare. In our cohort, PAX8 mutations were the leading cause of such a rare condition. ..
- Liu X, Yang Y, Yang Y, Lin X, Chen Y. [Novel NKX2-5 mutations identified in patients with congenital ventricular septal defects]. Zhonghua Yi Xue Za Zhi. 2009;89:2395-9 pubmed..63A > G: chi(2) = 3.403, P = 0.0651; c. 606G > C: chi(2) = 3.278, P = 0.0702). Novel NKX2-5 mutations are identified in patients with ASD. They may provide new insight into the molecular etiology responsible for VSD. ..
- Huang R, Xue S, Xu Y, Zhou M, Yang Y. A novel NKX2.5 loss-of-function mutation responsible for familial atrial fibrillation. Int J Mol Med. 2013;31:1119-26 pubmed publisher..The findings of the present study provide novel insights into the molecular mechanism underlying AF, suggesting the potential implications for the early prophylaxis and allele-specific therapy of AF. ..
- Ramos H, Nesi França S, Boldarine V, Pereira R, Chiamolera M, Camacho C, et al. Clinical and molecular analysis of thyroid hypoplasia: a population-based approach in southern Brazil. Thyroid. 2009;19:61-8 pubmed publisher..Clinical analysis revealed distinct hormonal patterns in TH subgroup when compared with other variants of TD, with genetic abnormalities identified only in few cases in the TSH-R, PAX8, and NKX2.5 genes. ..
- Liu Z, Li T, Liu Y, Jia Z, Li Y, Zhang C, et al. WNT signaling promotes Nkx2.5 expression and early cardiomyogenesis via downregulation of Hdac1. Biochim Biophys Acta. 2009;1793:300-11 pubmed publisher..Our data suggest that WNT signaling pathway plays important roles in the regulation of Hdac1 during the early stage of cardiomyocyte differentiation and that the downregulation of Hdac1 promotes cardiac differentiation. ..
- Akçaboy M, Cengiz F, Inceoglu B, Ucar T, Atalay S, Tutar E, et al. The effect of p.Arg25Cys alteration in NKX2-5 on conotruncal heart anomalies: mutation or polymorphism?. Pediatr Cardiol. 2008;29:126-9 pubmed..These results show that no genetic support exists for the pathogenecity of this alteration, although a previous in vitro study and theoretical predictions suggest a structural/functional difference in the altered protein region. ..
- Shiojima I, Komuro I, Inazawa J, Nakahori Y, Matsushita I, Abe T, et al. Assignment of cardiac homeobox gene CSX to human chromosome 5q34. Genomics. 1995;27:204-6 pubmed..Recently, a human cardiac homeobox-containing gene, CSX, has been isolated...
- Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, et al. Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease. J Biol Chem. 2000;275:35291-6 pubmedA homeodomain-containing transcription factor Csx/Nkx-2.5 is an important regulator of cardiogenesis in mammals...
- McElhinney D, Geiger E, Blinder J, Benson D, Goldmuntz E. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol. 2003;42:1650-5 pubmed..These findings suggest that NKX2.5 mutations in non-homeodomain regions may be important in the development of human structural cardiac defects. ..
- Schott J, Benson D, Basson C, Pease W, Silberbach G, Moak J, et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science. 1998;281:108-11 pubmed..These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life. ..
- Boldt L, Posch M, Perrot A, Polotzki M, Rolf S, Parwani A, et al. Mutational analysis of the PITX2 and NKX2-5 genes in patients with idiopathic atrial fibrillation. Int J Cardiol. 2010;145:316-317 pubmed publisher..Although we detected a number of variants, our candidate gene approach did not result in identification of mutations associated with AF in the coding regions of PITX2 or NKX2-5 in our well characterized AF cohort. ..
- Liu X, Yang Y, Yang Y, Lin X, Chen Y. [Mutation of NKX2-5 gene in patients with atrial septal defect]. Zhonghua Er Ke Za Zhi. 2009;47:696-700 pubmed..8641, P = 0.0906). A novel mutation of NKX2-5 gene identified in an ASD family suggests that mutated NKX2-5 gene is responsible for familial ASD. ..
- Ding J, Li K, Zhang X, Yao Y, Reng L, Tao S, et al. [Preliminary exploration of transcription factor Nkx2.5 mutations and congenital heart diseases]. Zhonghua Yi Xue Za Zhi. 2009;89:1114-6 pubmed..There are some associations between the Nkx2.5 gene mutation and occurrence of congenital heart disease in Chinese people. ..
- De Luca A, Sarkozy A, Ferese R, Consoli F, Lepri F, Dentici M, et al. New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle. Clin Genet. 2011;80:184-90 pubmed publisher..5 to a small number of TOF cases. ..
- Kasahara H, Izumo S. Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5. Mol Cell Biol. 1999;19:526-36 pubmedb>Csx/Nkx2.5, a member of the homeodomain-containing transcription factors, serves critical developmental functions in heart formation in vertebrates and nonvertebrates...
- Habets P, Moorman A, Clout D, van Roon M, Lingbeek M, Van Lohuizen M, et al. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev. 2002;16:1234-46 pubmed..5 on the ANF TBE-NKE, and was able to repress ANF promoter activity. Our data provide a potential mechanism for chamber-restricted gene activity in which the cooperative action of Tbx2 and Nkx2.5 inhibits expression in the AVC. ..
- Turbay D, Wechsler S, Blanchard K, Izumo S. Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx. Mol Med. 1996;2:86-96 pubmedb>Csx/Nkx2.5, a murine nonclustered homeobox gene expressed primarily in the heart, has significant sequence similarity to the Drosophila tinman gene. Tinman is essential for heart and gut formation in Drosophila...
- Risebro C, Petchey L, Smart N, Gomes J, Clark J, Vieira J, et al. Epistatic rescue of Nkx2.5 adult cardiac conduction disease phenotypes by prospero-related homeobox protein 1 and HDAC3. Circ Res. 2012;111:e19-31 pubmed publisher..5 function and establishes a model for ensuring electrophysiological function within the adult heart alongside insight into a novel Prox1-HDAC3-Nkx2.5 signaling pathway for therapeutic targeting in conduction disease. ..
- Reamon Buettner S, Hecker H, Spanel Borowski K, Craatz S, Kuenzel E, Borlak J. Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations. Am J Pathol. 2004;164:2117-25 pubmed..Further, observed mutations were completely absent in normal hearts and lymphocytic DNA of healthy individuals. Our findings provide new insights for somatic NKX2-5 mutations to be of importance in congenital heart disease. ..
- Riazi A, Lee H, Hsu C, Van Arsdell G. CSX/Nkx2.5 modulates differentiation of skeletal myoblasts and promotes differentiation into neuronal cells in vitro. J Biol Chem. 2005;280:10716-20 pubmedb>CSX/Nkx2.5 transcription factor plays a pivotal role in cardiac development; however, its role in development and differentiation of other organs has not been investigated...
- Pradhan L, Genis C, Scone P, Weinberg E, Kasahara H, Nam H. Crystal structure of the human NKX2.5 homeodomain in complex with DNA target. Biochemistry. 2012;51:6312-9 pubmed..This high resolution crystal structure of NKX2.5 protein provides a detailed picture of protein and DNA interactions, which allows us to predict DNA binding of mutants identified in human patients. ..
- van Engelen K, Mommersteeg M, Baars M, Lam J, Ilgun A, van Trotsenburg A, et al. The ambiguous role of NKX2-5 mutations in thyroid dysgenesis. PLoS ONE. 2012;7:e52685 pubmed publisher..Furthermore, given the wealth of published evidence, we suggest that NKX2-5 mutations do not play a major pathogenic role in thyroid dysgenesis, and that genetic testing of NKX2-5 in TD is not warranted. ..
- Durocher D, Charron F, Warren R, Schwartz R, Nemer M. The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. EMBO J. 1997;16:5687-96 pubmed..Given the co-expression of GATA proteins and NK2 class members in other tissues, the GATA/Nkx partnership may represent a paradigm for transcription factor interaction during organogenesis. ..
- Granados Riveron J, Pope M, Bu Lock F, Thornborough C, Eason J, Setchfield K, et al. Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations. Congenit Heart Dis. 2012;7:151-9 pubmed publisher..Our findings highlight the usefulness of multiple gene mutational analysis of large CHD cohorts. ..
- Esposito G, Butler T, Blue G, Cole A, Sholler G, Kirk E, et al. Somatic mutations in NKX2–5, GATA4, and HAND1 are not a common cause of tetralogy of Fallot or hypoplastic left heart. Am J Med Genet A. 2011;155A:2416-21 pubmed..No somatic or germline mutations were identified in the TOF or HLH patients. Although limited by sample size, our study suggests that somatic mutations in NKX2–5 and GATA4 are not a common cause of isolated TOF or HLH. ..
- Reamon Buettner S, Borlak J. Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease. J Med Genet. 2004;41:684-90 pubmed..Somatic mutations in transcription factor genes of cardiac progenitor cells provide a novel mechanism of disease. ..
- Zhang W, Li X, Ma Z, Zhang J, Zhou S, Li T, et al. GATA4 and NKX2.5 gene analysis in Chinese Uygur patients with congenital heart disease. Chin Med J (Engl). 2009;122:416-9 pubmed..There were no reported NKX2.5 mutations in the patients. Our results provided the primary data on CHD phenotype associated with GATA4 mutation in the Chinese Uygur population. ..
- Draus J, Hauck M, Goetsch M, Austin E, Tomita Mitchell A, Mitchell M. Investigation of somatic NKX2-5 mutations in congenital heart disease. J Med Genet. 2009;46:115-22 pubmed publisher..No evidence of somatic mutations was found in this study. Somatic mutations in NKX2-5 do not represent an important aetiologic pathway in pathologic cardiac development in patients with cardiac septal defects. ..
- Wang J, Zhang H, Iyer D, Feng X, Schwartz R. Regulation of cardiac specific nkx2.5 gene activity by small ubiquitin-like modifier. J Biol Chem. 2008;283:23235-43 pubmed publisher..SUMO conjugation stabilized the formation of Nkx2.5-containing complexes that led to robust transcriptional activation. Thus, SUMO modification serves as a positive regulator for Nkx2.5 transcriptional activity. ..
- Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, et al. Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet. 2001;28:276-80 pubmedThe cardiac homeobox protein Nkx2-5 is essential in cardiac development, and mutations in Csx (which encodes Nkx2-5) cause various congenital heart diseases...
- Brust E, Beltrão C, Chammas M, Watanabe T, Sapienza M, Marui S. Absence of mutations in PAX8, NKX2.5, and TSH receptor genes in patients with thyroid dysgenesis. Arq Bras Endocrinol Metabol. 2012;56:173-7 pubmed..No mutations were detected in any of the genes studied. Sporadic cases of TD are likely to be caused by epigenetic factors, rather than mutations in thyroid transcription factors or genes involved in thyroid development. ..
- Xie W, Chang C, Xu Y, Li R, Qu X, Fang W, et al. Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation. Clinics (Sao Paulo). 2013;68:777-84 pubmed publisher..These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia. ..
- Pashmforoush M, Lu J, Chen H, Amand T, Kondo R, Pradervand S, et al. Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell. 2004;117:373-86 pubmed..Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease. ..
- Harvey R, Lai D, Elliott D, Biben C, Solloway M, Prall O, et al. Homeodomain factor Nkx2-5 in heart development and disease. Cold Spring Harb Symp Quant Biol. 2002;67:107-14 pubmed
- Wang J, Lu Y, Chen H, Yin M, Yu T, Fu Q. Investigation of somatic NKX2-5, GATA4 and HAND1 mutations in patients with tetralogy of Fallot. Pathology. 2011;43:322-6 pubmed publisher..Our study shows no evidence of somatic NKX2-5, GATA4 and HAND1 mutations playing a role in the pathogenesis of TOF. Our findings suggest that the GATA4 and HAND1 germline mutations are associated with non-syndromic CHD. ..
- Caprioli A, Koyano Nakagawa N, Iacovino M, Shi X, Ferdous A, Harvey R, et al. Nkx2-5 represses Gata1 gene expression and modulates the cellular fate of cardiac progenitors during embryogenesis. Circulation. 2011;123:1633-41 pubmed publisher..Our results demonstrate that the hematopoietic/erythroid cell fate is suppressed via Nkx2-5 during mesodermal fate determination, and that the Gata1 gene is one of the targets that are suppressed by Nkx2-5. ..
- Briggs L, Takeda M, Cuadra A, Wakimoto H, Marks M, Walker A, et al. Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects. Circ Res. 2008;103:580-90 pubmed publisher..These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction. ..
- Garg V, Kathiriya I, Barnes R, Schluterman M, King I, Butler C, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003;424:443-7 pubmed..These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5. ..
- Elliott D, Kirk E, Yeoh T, Chandar S, McKenzie F, Taylor P, et al. Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. J Am Coll Cardiol. 2003;41:2072-6 pubmed..Screening for NKX2-5 mutations may be warranted in individuals with ASD and a positive family history, irrespective of the presence or absence of AV conduction block. ..
- Benson D, Silberbach G, Kavanaugh McHugh A, Cottrill C, Zhang Y, Riggs S, et al. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999;104:1567-73 pubmed..The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways. ..
- Stallmeyer B, Fenge H, Nowak Gottl U, Schulze Bahr E. Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease. Clin Genet. 2010;78:533-40 pubmed publisher..Thus, even important for cardiac development, germline mutations in NKX2.5 are rare in patients with sporadic CHD and genetic and/or pathophysiologic heterogeneity is likely for sporadic forms of CHD. ..
- Kasahara H, Lee B, Schott J, Benson D, Seidman J, Seidman C, et al. Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease. J Clin Invest. 2000;106:299-308 pubmedb>CSX/NKX2.5 is an evolutionarily conserved homeodomain-containing (HD-containing) transcription factor that is essential for early cardiac development. Recently, ten different heterozygous CSX/NKX2...
- Goldmuntz E, Geiger E, Benson D. NKX2.5 mutations in patients with tetralogy of fallot. Circulation. 2001;104:2565-8 pubmed
- Chen C, Schwartz R. Recruitment of the tinman homolog Nkx-2.5 by serum response factor activates cardiac alpha-actin gene transcription. Mol Cell Biol. 1996;16:6372-84 pubmed..5 homeodomain and to the N-terminal extension of the MADS box. Our study suggests that physical association between Nkx-2.5 and SRF is one way that cardiac specified genes are activated in cardiac cell lineages. ..
- Pfeufer A, van Noord C, Marciante K, Arking D, Larson M, Smith A, et al. Genome-wide association study of PR interval. Nat Genet. 2010;42:153-9 pubmed publisher..Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes...
- Kontaraki J, Kochiadakis G, Marketou M, Chlouverakis G, Igoumenidis N, Saloustros I, et al. Early cardiac gene transcript levels in peripheral blood mononuclear cells reflect severity in stable coronary artery disease. Hellenic J Cardiol. 2014;55:119-25 pubmed
- Verbij F, Stokhuijzen E, Kaijen P, van Alphen F, Meijer A, Voorberg J. Identification of glycans on plasma-derived ADAMTS13. Blood. 2016;128:e51-e58 pubmed..This O-fucosylation site did not meet the proposed consensus sequence CSX(S/T)CG. C-mannosylation sites were identified in TSP1, linker TSP4-TSP5, and TSP8...
- Zhang J, Cheng Y, Duan M, Qi N, Liu J. Unveiling differentially expressed genes upon regulation of transcription factors in sepsis. 3 Biotech. 2017;7:46 pubmed publisher..The identified eight DEGs may be regarded as the diagnosis marker and drug target for sepsis. ..
- Maioli M, Santaniello S, Montella A, Bandiera P, Cantoni S, Cavallini C, et al. Hyaluronan esters drive Smad gene expression and signaling enhancing cardiogenesis in mouse embryonic and human mesenchymal stem cells. PLoS ONE. 2010;5:e15151 pubmed publisher..We have recently developed hyaluronan mixed esters of butyric and retinoic acids (HBR), turning cardiovascular stem cell fate into a high-yield process. The HBR mechanism(s) remain still largely undefined...
- Venturin M, Bentivegna A, Moroni R, Larizza L, Riva P. Evidence by expression analysis of candidate genes for congenital heart defects in the NF1 microdeletion interval. Ann Hum Genet. 2005;69:508-16 pubmed
- Månsson Broberg A, Rodin S, Bulatovic I, Ibarra C, Löfling M, Genead R, et al. Wnt/?-Catenin Stimulation and Laminins Support Cardiovascular Cell Progenitor Expansion from Human Fetal Cardiac Mesenchymal Stromal Cells. Stem Cell Reports. 2016;6:607-617 pubmed publisher..Our protocol for large-scale culture of human fetal cardiac MSCs enables future exploration of the regenerative functions of these cells in the context of myocardial injury in vitro and in vivo. ..