Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum

Journal of Medical Genetics

Volumn 51, Issue 6, 2014, Pages 375-387

  Thorwarth, Anne ^a,b   Sarah, Schnittert Hübener ^a   Schrumpf, Pamela ^a   Müller, Ines ^b   Jyrch, Sabine ^a   Dame, Christof ^a   Biebermann, Heike ^a   Kleinau, Gunnar ^a   Katchanov, Juri ^a   Schuelke, Markus ^a   Ebert, Grit ^b   Steininger, Anne ^b   Bönnemann, Carsten ^c   Brockmann, Knut ^d   Christen, Hans Jürgen ^e   Crock, Patricia ^f   deZegher, Francis ^g   Griese, Matthias ^h   Hewitt, Jacqueline ⁱ   Ivarsson, Sten ^j   Hübner, Christoph ^a   Kapelari, Klaus ^k   Plecko, Barbara ^l   Rating, Dietz ^m   Stoeva, Iva ⁿ   Ropers, Hans Hilger ^b,o   Grüters, Annette ^a   Ullmann, Reinhard ^b   Krude, Heiko ^a   more..

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^b MAX PLANCK INSTITUTE FOR MOLECULAR GENETICS   (Germany)

^c NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE   (United States)

^d UNIVERSITY OF GÖTTINGEN   (Germany)

^e Children's Hospital Auf der Bult   (Germany)

^f JOHN HUNTER CHILDREN S HOSPITAL   (Australia)

^g UNIVERSITY OF LEUVEN   (Belgium)

^h LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

ⁱ ROYAL CHILDREN'S HOSPITAL   (Australia)

^j LUND UNIVERSITY HOSPITAL   (Sweden)

^k INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^l UNIVERSITY CHILDREN S HOSPITAL   (Switzerland)

^m UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

ⁿ MEDICAL UNIVERSITY OF SOFIA   (Bulgaria)

^o UNIVERSITY OF ULM   (Germany)

more..

Author keywords

[No Author keywords available]

Indexed keywords

TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR NKX2.1; UNCLASSIFIED DRUG; NUCLEAR PROTEIN; THYROID NUCLEAR FACTOR 1;

ADOLESCENT; ADULT; ARTICLE; ASTHMA; ATTENTION DISTURBANCE; BODY HEIGHT; CHILD; COPY NUMBER VARIATION; DYSARTHRIA; FEMALE; FEVER; FRAMESHIFT MUTATION; GEL MOBILITY SHIFT ASSAY; GENE EXPRESSION; GENE FREQUENCY; GENE MUTATION; GENETIC ASSOCIATION; GENOMICS; GENOTYPE; HEART SEPTUM DEFECT; HUMAN; IN SITU HYBRIDIZATION; INDEL MUTATION; INFANT; INTELLIGENCE QUOTIENT; MAJOR CLINICAL STUDY; MALE; MISSENSE MUTATION; MOTOR DYSFUNCTION; MUTATION RATE; NEUROLOGIC DISEASE; NEWBORN; NUCLEOTIDE SEQUENCE; PHENOTYPE; PNEUMONIA; POINT MUTATION; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN DNA BINDING; RESPIRATORY DISTRESS SYNDROME; THYROID DISEASE; THYROID DYSGENESIS; COMPARATIVE GENOMIC HYBRIDIZATION; GENE DELETION; GENETIC DISORDER; GENETICS; PATHOPHYSIOLOGY; PRESCHOOL CHILD;

MURINAE;

ADOLESCENT; CHILD; CHILD, PRESCHOOL; COMPARATIVE GENOMIC HYBRIDIZATION; DNA COPY NUMBER VARIATIONS; ELECTROPHORETIC MOBILITY SHIFT ASSAY; FEMALE; GENE DELETION; GENETIC DISEASES, INBORN; HUMANS; INFANT; INFANT, NEWBORN; MALE; NUCLEAR PROTEINS; PHENOTYPE; POINT MUTATION; TRANSCRIPTION FACTORS;

EID: 84901454226     PISSN: 00222593     EISSN: 14686244     Source Type: Journal    
DOI: 10.1136/jmedgenet-2013-102248     Document Type: Article

References (87)

1. Kim Y, Nirenberg M. Drosophila NK-homeobox genes. Proc Natl Acad Sci USA 1989;86:7716-20.
2. Guazzi S, Price M, De Felice M, Damante G, Mattei MG, Di Lauro R. Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J 1990;9:3631-9.
3. Mizuno K, Gonzalez FJ, Kimura S. Thyroid-specific enhancer-binding protein (T/EBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1. Mol Cell Biol 1991;11:4927-33.
4. Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, Gonzalez FJ. 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 1996;10:60-9.
5. Sussel L, Marin O, Kimura S, Rubenstein JL. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development 1999;126:3359-70.
6. 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. N Engl J Med 1998;338:1317-18.
7. 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 Pediatr 2000;137:272-6.
8. 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;109:475-80.
9. Pohlenz J, Dumitrescu A, Zundel D, Martine U, Schonberger W, Koo E, Weiss RE, Cohen RN, Kimura S, Refetoff S. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice. J Clin Invest 2002;109:469-73.
10. Breedveld GJ, van Dongen JW, Danesino C, Guala A, Percy AK, Dure LS, Harper P, Lazarou LP, van der Linde H, Joosse M, Gruters A, MacDonald ME, de Vries BB, Arts WF, Oostra BA, Krude H, Heutink P. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 2002;11:971-9.
11. Petek E, Plecko-Startinig B, Windpassinger C, Egger H, Wagner K, Kroisel PM. Molecular characterisation of a 3.5 Mb interstitial 14q deletion in a child with several phenotypic anomalies. J Med Genet A 2003;40:e47.
12. Devos D, Vuillaume I, de Becdelievre A, de Martinville B, Dhaenens CM, Cuvellier JC, Cuisset JM, Vallee L, Lemaitre MP, Bourteel H, Hachulla E, Wallaert B, Destee A, Defebvre L, Sablonniere B. New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes. Mov Disord 2006;21:2237-40.
13. 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;18:2266-76.
14. Teissier R, Guillot L, Carre A, Morandini M, Stuckens C, Ythier H, Munnich A, Szinnai G, de Blic J, Clement A, Leger J, Castanet M, Epaud R, Polak M. Multiplex Ligation-dependent Probe Amplification improves the detection rate of NKX2.1 mutations in patients affected by brain-lung-thyroid syndrome. Horm Res Paediatr 2012;77:146-51.
15. Gras D, Jonard L, Roze E, Chantot-Bastaraud S, Koht J, Motte J, Rodriguez D, Louha M, Caubel I, Kemlin I, Lion-Francois L, Goizet C, Guillot L, Moutard ML, Epaud R, Heron B, Charles P, Tallot M, Camuzat A, Durr A, Polak M, Devos D, Sanlaville D, Vuillaume I, Billette de Villemeur T, Vidailhet M, Doummar D. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. J Neurol Neurosurg Psychiatry 2012;83:956-62.
16. Santen GW, Sun Y, Gijsbers AC, Carre A, Holvoet M, Haeringen A, Lesnik Oberstein SA, Tomoda A, Mabe H, Polak M, Devriendt K, Ruivenkamp CA, Bijlsma EK. Further delineation of the phenotype of chromosome 14q13 deletions: ( positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus. J Med Genet A 2012;49:366-72.
17. Willemsen MA, Breedveld GJ, Wouda S, Otten BJ, Yntema JL, Lammens M, de Vries BB. Brain-Thyroid-Lung syndrome: a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr 2005;164:28-30.
18. Moya CM, Perez de Nanclares G, Castano L, Potau N, Bilbao JR, Carrascosa A, Bargada M, Coya R, Martul P, Vicens-Calvet E, Santisteban P. 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 2006;91:1832-41.
19. Nagasaki K, Narumi S, Asami T, Kikuchi T, Hasegawa T, Uchiyama M. Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin. Endocr J 2008;55:875-8.
20. Kleinlein B, Griese M, Liebisch G, Krude H, Lohse P, Aslanidis C, Schmitz G, Peters J, Holzinger A. Fatal neonatal respiratory failure in an infant with congenital hypothyroidism due to haploinsufficiency of the NKX2-1 gene: alteration of pulmonary surfactant homeostasis. Arch Dis Child 2010.
21. Nettore IC, Ferrara AM, Mirra P, Sibilio A, Pagliara V, Kamoi Kay CS, Lorenzoni PJ, Werneck LC, Bruck I, Coutinho 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;23:675-82.
22. 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 2005;64:1952-4.
23. do Carmo Costa M, Costa C, Silva AP, Evangelista P, Santos L, Ferro A, Sequeiros J, Maciel P. Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. Neurogenetics 2005;6:209-15.
24. Provenzano C, Veneziano L, Appleton R, Frontali M, Civitareale D. Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. J Neurol Sci 2008;264:56-62.
25. Glik A, Vuillaume I, Devos D, Inzelberg R. Psychosis, short stature in benign hereditary chorea: a novel thyroid transcription factor-1 mutation. Mov Disord 2008;23:1744-7.
26. Ferrara AM, De Michele G, Salvatore E, Di Maio L, Zampella E, Capuano S, Del Prete G, Rossi G, Fenzi G, Filla A, Macchia PE. A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea. Thyroid 2008;18:1005-9.
27. Maquet E, Costagliola S, Parma J, Christophe-Hobertus C, Oligny LL, Fournet JC, Robitaille Y, Vuissoz JM, Payot A, Laberge S, Vassart G, Van Vliet G, Deladoey J. Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene. J Clin Endocrinol Metab 2009;94:197-203.
28. Gillett ES, Deutsch GH, Bamshad MJ, McAdams RM, Mann PC. Novel NKX2.1 mutation associated with hypothyroidism and lethal respiratory failure in a full-term neonate. J Perinatol 2013;33:157-60.
29. Kleiner-Fisman G, Rogaeva E, Halliday W, Houle S, Kawarai T, Sato C, Medeiros H, St George-Hyslop PH, Lang AE. Benign hereditary chorea: clinical, genetic, and pathological findings. Ann Neurol 2003;54:244-7.
30. Doyle DA, 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 Pediatr 2004;145:190-3.
31. Asmus F, Devlin A, Munz M, Zimprich A, Gasser T, Chinnery PF. Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia. Mov Disord 2007;22:2104-9.
32. Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK, Alfano DN, Halbower AC, Planer B, Stephan MJ, Uchida DA, Williames LD, Rosenfeld JA, Lebel RR, Young LR, Cole FS, Nogee LM. Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1. Chest 2013;144:794-804.
33. Salerno T, Peca D, Menchini L, Schiavino A, Petreschi F, Occasi F, Cogo P, Danhaive O, Cutrera R. Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene. Pediatr Pulmonol 2013;49:E42-4.
34. Stockton DW, Das P, Goldenberg M, D'Souza RN, Patel PI. Mutation of PAX9 is associated with oligodontia. Nat Genet 2000;24:18-19.
35. Devos H, Rodd C, Gagne N, Laframboise R, Van Vliet G. A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab 1999;84:2502-6.
36. Guala A, Falco V, Breedveld G, De Filippi P, Danesino C. Deletion of PAX9 and oligodontia: a third family and review of the literature. Int J Paediatr Dent 2008;18:441-5.
37. Silberschmidt D, Rodriguez-Mallon A, Mithboakar P, Cali G, Amendola E, Sanges R, Zannini M, Scarfo M, De Luca P, Nitsch L, Di Lauro R, De Felice M. In vivo role of different domains and of phosphorylation in the transcription factor Nkx2-1. BMC Dev Biol 2011;11:9.
38. Inzelberg R, Weinberger M, Gak E. Benign hereditary chorea: an update. Parkinsonism Relat Disord 2011;17:301-7.
39. Dale RC, Grattan-Smith P, Nicholson M, Peters GB. Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study. Dev Med Child Neurol 2012;54:618-23.
40. Esposito G, Fogolari F, Damante G, Formisano S, Tell G, Leonardi A, Di Lauro R, Viglino P. Analysis of the solution structure of the homeodomain of rat thyroid transcription factor 1 by 1H-NMR spectroscopy and restrained molecular mechanics. Eur J Biochem/FEBS 1996;241:101-13.
41. Al Taji E, Biebermann H, Limanova Z, Hnikova O, Zikmund J, Dame C, Gruters A, Lebl J, Krude H. 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 2007;156:521-9.
42. Dame C, Sola MC, Lim KC, Leach KM, Fandrey J, Ma Y, Knopfle G, Engel JD, Bungert J. Hepatic erythropoietin gene regulation by GATA-4. J Biol Chem 2004;279:2955-61.
43. Civitareale D, Lonigro R, Sinclair AJ, Di Lauro R. A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. EMBO J 1989;8:2537-42.
44. de Sanctis L, Corrias A, Romagnolo D, Di Palma T, Biava A, Borgarello G, Gianino P, Silvestro L, Zannini M, Dianzani I. Familial PAX8 small deletion (c.989_992delACCC) associated with extreme phenotype variability. J Clin Endocrinol Metab 2004;89:5669-74.
45. Musti AM, Avvedimento EV, Polistina C, Ursini VM, Obici S, Nitsch L, Cocozza S, Di Lauro R. The complete structure of the rat thyroglobulin gene. Proc Natl Acad Sci USA 1986;83:323-7.
46. Tucker ES, Segall S, Gopalakrishna D, Wu Y, Vernon M, Polleux F, Lamantia AS. Molecular specification and patterning of progenitor cells in the lateral and medial ganglionic eminences. J Neurosci 2008;28:9504-18.
47. Brent AE, Schweitzer R, Tabin CJ. A somitic compartment of tendon progenitors. Cell 2003;113:235-48.
48. Dessau RB, Pipper CB. ["R"--project for statistical computing]. Ugeskr Laeger 2008;170:328-30.
49. Antonica F, Kasprzyk DF, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, Refetoff S, Peremans K, Manto M, Kyba M, Costagliola S. Generation of functional thyroid from embryonic stem cells. Nature 2012;491:66-71.
50. Lapi P, Macchia PE, Chiovato L, Biffali E, Moschini L, Larizza D, Baserga M, Pinchera A, Fenzi G, Di Lauro R. Mutations in the gene encoding thyroid transcription factor-1 (TTF-1) are not a frequent cause of congenital hypothyroidism (CH) with thyroid dysgenesis. Thyroid 1997;7:383-7.
51. Perna MG, Civitareale D, De Filippis V, Sacco M, Cisternino C, Tassi V. Absence of mutations in the gene encoding thyroid transcription factor-1 (TTF-1) in patients with thyroid dysgenesis. Thyroid 1997;7:377-81.
52. Hishinuma A, Kuribayashi T, Kanno Y, Onigata K, Nagashima K, Ieiri T. Sequence analysis of thyroid transcription factor-1 gene reveals absence of mutations in patients with thyroid dysgenesis but presence of polymorphisms in the 5' flanking region and intron. Endocr J 1998;45:563-7.
53. Germain ND, Banda EC, Becker S, Naegele JR, Grabel LB. Derivation and isolation of NKX2.1-positive basal forebrain progenitors from human embryonic stem cells. Stem Cells Dev 2013;22:1477-89.
54. Niquille M, Minocha S, Hornung JP, Rufer N, Valloton D, Kessaris N, Alfonsi F, Vitalis T, Yanagawa Y, Devenoges C, Dayer A, Lebrand C. Two specific populations of GABAergic neurons originating from the medial and the caudal ganglionic eminences aid in proper navigation of callosal axons. Dev Neurobiol 2013;73:647-72.
55. Zhao Y, Flandin P, Vogt D, Blood A, Hermesz E, Westphal H, Rubenstein J. Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon. Dev Biol 2013;385:94-106.
56. Woods JO, Singh-Blom UM, Laurent JM, McGary KL, Marcotte EM. Prediction of gene-phenotype associations in humans, mice, and plants using phenologs. BMC Bioinformatics 2013;14:203.
57. Olivieri A, Stazi MA, Mastroiacovo P, Fazzini C, Medda E, Spagnolo A, De Angelis S, Grandolfo ME, Taruscio D, Cordeddu V, Sorcini M. A population-based study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital Hypothyroidism (1991-1998). J Clin Endocrinol Metab 2002;87:557-62.
58. van Tuyl M, Blommaart PE, de Boer PA, Wert SE, Ruijter JM, Islam S, Schnitzer J, Ellison AR, Tibboel D, Moorman AF, Lamers WH. Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs. Dev Biol 2004;272:104-17.
59. Ching YH, Ghosh TK, Cross SJ, Packham EA, Honeyman L, Loughna S, Robinson TE, Dearlove AM, Ribas G, Bonser AJ, Thomas NR, Scotter AJ, Caves LS, Tyrrell GP, Newbury-Ecob RA, Munnich A, Bonnet D, Brook JD. Mutation in myosin heavy chain 6 causes atrial septal defect. Nat Genet 2005;37:423-8.
60. Ngan ES, Lang BH, Liu T, Shum CK, So MT, Lau DK, Leon TY, Cherny SS, Tsai SY, Lo CY, Khoo US, Tam PK, Garcia-Barcelo MM. A germline mutation (A339 V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma. J Natl Cancer Inst 2009;101:162-75.
61. Zhang Y, Rath N, Hannenhalli S, Wang Z, Cappola T, Kimura S, Atochina-Vasserman E, Lu MM, Beers MF, Morrisey EE. GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo. Development 2007;134:189-98.
62. Trivedi CM, Zhu W, Wang Q, Jia C, Kee HJ, Li L, Hannenhalli S, Epstein JA. Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation. Dev Cell 2010;19:450-9.
63. Brewer AC, Alexandrovich A, Mjaatvedt CH, Shah AM, Patient RK, Pizzey JA. GATA factors lie upstream of Nkx 2.5 in the transcriptional regulatory cascade that effects cardiogenesis. Stem Cells Dev 2005;14:425-39.
64. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M. Characterizing the cancer genome in lung adenocarcinoma. Nature 2007;450:893-8.
65. Kendall J, Liu Q, Bakleh A, Krasnitz A, Nguyen KC, Lakshmi B, Gerald WL, Powers S, Mu D. Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer. Proc Natl Acad Sci U S A 2007;104:16663-8.
66. Homminga I, Pieters R, Langerak AW, de Rooi JJ, Stubbs A, Verstegen M, Vuerhard M, Buijs-Gladdines J, Kooi C, Klous P, van Vlierberghe P, Ferrando AA, Cayuela JM, Verhaaf B, Beverloo HB, Horstmann M, de Haas V, Wiekmeijer AS, Pike-Overzet K, Staal FJ, de Laat W, Soulier J, Sigaux F, Meijerink JP. Integrated Transcript and Genome Analyses Reveal NKX2-1 and MEF2C as Potential Oncogenes in T Cell Acute Lymphoblastic Leukemia. Cancer Cell 2011;19:484-97.
67. Fabbro D, Di Loreto C, Beltrami CA, Belfiore A, Di Lauro R, Damante G. Expression of thyroid-specific transcription factors TTF-1 and PAX-8 in human thyroid neoplasms. Cancer Res 1994;54:4744-9.
68. Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Sigurdsson A, Bergthorsson JT, He H, Blondal T, Geller F, Jakobsdottir M, Magnusdottir DN, Matthiasdottir S, Stacey SN, Skarphedinsson OB, Helgadottir H, Li W, Nagy R, Aguillo E, Faure E, Prats E, Saez B, Martinez M, Eyjolfsson GI, Bjornsdottir US, Holm H, Kristjansson K, Frigge ML, Kristvinsson H, Gulcher JR, Jonsson T, Rafnar T, Hjartarsson H, Mayordomo JI, de la Chapelle A, Hrafnkelsson J, Thorsteinsdottir U, Kong A, Stefansson K. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet 2009;41:460-4.
69. Matsuse M, Mitsutake N, Tanimura S, Ogi T, Nishihara E, Hirokawa M, Fuziwara CS, Saenko VA, Suzuki K, Miyauchi A, Yamashita S. Functional characterization of the novel BRAF complex mutation, BRAF(V600delinsYM) , identified in papillary thyroid carcinoma. Int J Cancer 2013;132:738-43.
70. Fernandez M, Raskind W, Matsushita M, Wolff J, Lipe H, Bird T. Hereditary benign chorea: clinical and genetic features of a distinct disease. Neurology 2001;57:106-10.
71. Kleiner-Fisman G, Lang AE. Benign hereditary chorea revisited: A journey to understanding. Mov Disord 2007;22:2297-305.
72. Minoo P, Hu L, Xing Y, Zhu NL, Chen H, Li M, Borok Z, Li C. Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells. Mol Cell Biol 2007;27:2155-65.
73. Ku MS, Sun HL, Lu KH, Sheu JN, Lee HS, Yang SF, Lue KH. The CC16 A38G polymorphism is associated with the development of asthma in children with allergic rhinitis. Clin Exp Allergy 2011;41:794-800.
74. Puthothu B, Krueger M, Heinze J, Forster J, Heinzmann A. Haplotypes of surfactant protein C are associated with common paediatric lung diseases. Pediatr Allergy Immunol 2006;17:572-7.
75. Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK, Alfano DN, Halbower AC, Planer B, Stephan MJ, Uchida DA, Williames LD, Rosenfeld JA, Lebel RR, Young LR, Cole FS, Nogee LM. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 2013;144:794-804.
76. Yin Z, Gonzales L, Kolla V, Rath N, Zhang Y, Lu MM, Kimura S, Ballard PL, Beers MF, Epstein JA, Morrisey EE. Hop functions downstream of Nkx2.1 and GATA6 to mediate HDAC-dependent negative regulation of pulmonary gene expression. Am J Physiol Lung Cell Mol Physiol 2006;291:L191-9.
77. Barnett CP, Mencel JJ, Gecz J, Waters W, Kirwin SM, Vinette KM, Uppill M, Nicholl J. Choreoathetosis, congenital hypothyroidism and neonatal respiratory distress syndrome with intact NKX2-1. Am J Med Genet A 2012;158A: 3168-73.
78. Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M, Minovitsky S, Dubchak I, Holt A, Lewis KD, Plajzer-Frick I, Akiyama J, De Val S, Afzal V, Black BL, Couronne O, Eisen MB, Visel A, Rubin EM. In vivo enhancer analysis of human conserved non-coding sequences. Nature 2006;444:499-502.
79. Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, Bos SD, Deelen J, den Heijer M, Freathy RM, Lahti J, Liu C, Lopez LM, Nolte IM, O'Connell JR, Tanaka T, Trompet S, Arnold A, Bandinelli S, Beekman M, Bohringer S, Brown SJ, Buckley BM, Camaschella C, de Craen AJ, Davies G, de Visser MC, Ford I, Forsen T, Frayling TM, Fugazzola L, Gogele M, Hattersley AT, Hermus AR, Hofman A, Houwing-Duistermaat JJ, Jensen RA, Kajantie E, Kloppenburg M, Lim EM, Masciullo C, Mariotti S, Minelli C, Mitchell BD, Nagaraja R, Netea-Maier RT, Palotie A, Persani L, Piras MG, Psaty BM, Raikkonen K, Richards JB, Rivadeneira F, Sala C, Sabra MM, Sattar N, Shields BM, Soranzo N, Starr JM, Stott DJ, Sweep FC, Usala G, van der Klauw MM, van Heemst D, van Mullem A, Vermeulen SH, Visser WE, Walsh JP, Westendorp RG, Widen E, Zhai G, Cucca F, Deary IJ, Eriksson JG, Ferrucci L, Fox CS, Jukema JW, Kiemeney LA, Pramstaller PP, Schlessinger D, Shuldiner AR, Slagboom EP, Uitterlinden AG, Vaidya B, Visser TJ, Wolffenbuttel BH, Meulenbelt I, Rotter JI, Spector TD, Hicks AA, Toniolo D, Sanna S, Peeters RP, Naitza S. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS genetics 2013;9:e1003266.
80. Zhou X, Maricque B, Xie M, Li D, Sundaram V, Martin EA, Koebbe BC, Nielsen C, Hirst M, Farnham P, Kuhn RM, Zhu J, Smirnov I, Kent WJ, Haussler D, Madden PA, Costello JF, Wang T. The Human Epigenome Browser at Washington University. Nat Methods 2011;8:989-90.
81. Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, Lee K, Canfield T, Weaver M, Sandstrom R, Thurman RE, Kaul R, Myers RM, Stamatoyannopoulos JA. Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res 2012;22:1680-8.
82. Li G, Fullwood MJ, Xu H, Mulawadi FH, Velkov S, Vega V, Ariyaratne PN, Mohamed YB, Ooi HS, Tennakoon C, Wei CL, Ruan Y, Sung WK. ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing. Genome Biol 2010;11:R22.
83. Santagati F, Abe K, Schmidt V, Schmitt-John T, Suzuki M, Yamamura K, Imai K. Identification of Cis-regulatory elements in the mouse Pax9/Nkx2-9 genomic region: implication for evolutionary conserved synteny. Genetics 2003;165:235-42.
84. Wang YL, Faiola F, Xu M, Pan S, Martinez E. Human ATAC Is a GCN5/ PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein. J Biol Chem 2008;283:33808-15.
85. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C, Jensen LJ. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 2013;41(Database issue):D808-15.
86. Hamdan H, Liu H, Li C, Jones C, Lee M, deLemos R, Minoo P. Structure of the human Nkx2.1 gene. Biochim Biophys Acta 1998;1396:336-48.
87. Ikeda K, Clark JC, Shaw-White JR, Stahlman MT, Boutell CJ, Whitsett JA. Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells. J Biol Chem 1995;270:8108-14.