Partial deficiency of Thyroid transcription factor 1 produces predominantly neurological defects in humans and mice

Pohlenz, Joachim; Dumitrescu, A; Zundel, Dorothee; Martiné, Ursula; Schönberger, W; Koo, Eugene; Weiss, Roy E.; Cohen, Ronald N.; Kimura, Shioko; Refetoff, Samuel

doi:10.1172/jci0214192

Cited by 168 publications

(113 citation statements)

References 25 publications

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“…26,27 Furthermore, recently, heterozygous mutations of TTF1 (or NKX2.1) have been identified in patients with a normal or hypoplastic thyroid gland. 28,29 Taken together, these data support the involvement of these four genes in thyroid development in mice and humans. However, despite extensive searches for mutation in these candidate genes, only a handful of TD cases have been satisfactorily explained on their basis, and their involvement in the general TD population remains questionable.…”

Section: Introductionsupporting

confidence: 69%

Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes

et al. 2004

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The pathophysiology of thyroid dysgenesis (TD) is not elucidated yet in the majority of cases. The unexpected familial clustering of congenital hypothyroidism due to TD suggests a genetically determined disorder. Four genes have been hitherto involved in thyroid development, including migration and growth. Three of these encode transcription factors (the thyroid transcription factors 1 and 2 (TTF1 or NKX2.1 and TTF2 or FOXE1) and PAX8) while the other encodes the thyrotropin hormone receptor (TSHR). Some mutations have been reported in patients affected by thyroid defects, which supports the relevance of these four genes in TD. However, their involvement in the general TD population remains questionable. Therefore, to document their involvement, we performed a linkage analysis followed by mutational analysis in 19 multiplex TD families. The LOD score results failed to prove linkage between any of the four genes and the TD phenotype, whatever the postulated mode of inheritance. Manual extended haplotypes showed allele sharing among affected individuals of at least one of these four genes in the majority of families. Nevertheless, mutational analysis did not identify mutations in these cases, arguing in favor of identity by descent and not identity by state. Furthermore, as a main result of the present study, extended haplotypes confirmed by mutational analysis showed that the four genes were excluded in five out of the 19 investigated families, demonstrating the relevance of other genes. In conclusion, the present study demonstrates genetic heterogeneity in the TD disorder and suggests the involvement of novel genes.

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Section: Introductionsupporting

confidence: 69%

Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes

et al. 2004

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“…Human embryonic kidney cells HEK293 (ATCC, CRL-1573) were grown as described previously [Carre et al, 2009]. The reporter gene containing NKX2-1 and PAX8 binding sites from the TG promoter upstream of luciferase was used [Pohlenz et al, 2002]. Cells were plated at 2x10 5 cells per well in a 24-well plate 24 h before transfection.…”

Section: Cell Culture and Transactivation Experimentsmentioning

confidence: 99%

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

et al. 2010

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NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the surfactant protein (SP)-B and -C genes (SFTPB and SFTPC, respectively). We identified and functionally characterized two new de novo NKX2-1 mutations c.493C>T (p.R165W) and c.786_787del2 (p.L263fs) in infants with closely similar severe interstitial lung disease (ILD), hypotonia, and congenital hypothyroidism. Functional analyses using A549 and HeLa cells revealed that NKX2-1-p.L263fs induced neither SFTPB nor SFTPC promoter activation and had a dominant negative effect on wild-type (WT) NKX2-1. In contrast, NKX2-1-p.R165W activated SFTPC, to a significantly greater extent than did WT NKX2-1, while SFTPB activation was only significantly reduced in HeLa cells. In accordance with our in vitro data, we found decreased amounts of SP-B and SP-C by western blot in bronchoalveolar lavage fluid (patient with p.L263fs) and features of altered surfactant protein metabolism on lung histology (patient with NKX2-1-p.R165W). In conclusion, ILD in patients with NKX2-1 mutations was associated with altered surfactant protein metabolism, and both gain and loss of function of the mutated NKX2-1 genes on surfactant protein promoters were associated with ILD in "Brain-Lung-Thyroid syndrome".

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“…Our finding that Gata6 can act as a modifier of Nkx2.1 may help to explain why some human patients with NKX2.1 mutations have respiratory defects whereas others appear normal (Krude et al, 2002;Pohlenz et al, 2002). The gene-expression defects uncovered in G6-Nkx DH embryos and mice represent targets that are specifically regulated by the synergistic activity of these two transcription factors.…”

Section: Research Articlementioning

confidence: 84%

GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo

et al. 2007

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In vitro studies have suggested that members of the GATA and Nkx transcription factor families physically interact, and synergistically activate pulmonary epithelial-and cardiac-gene promoters. However, the relevance of this synergy has not been demonstrated in vivo. We show that Gata6-Titf1 (Gata6-Nkx2.1) double heterozygous (G6-Nkx DH) embryos and mice have severe defects in pulmonary epithelial differentiation and distal airway development, as well as reduced phospholipid production. The defects in G6-Nkx DH embryos and mice are similar to those observed in human neonates with respiratory distress syndromes, including bronchopulmonary dysplasia, and differential gene expression analysis reveals essential developmental pathways requiring synergistic regulation by both Gata6 and Titf1 (Nkx2.1). These studies indicate that Gata6 and Nkx2.1 act in a synergistic manner to direct pulmonary epithelial differentiation and development in vivo, providing direct evidence that interactions between these two transcription factor families are crucial for the development of the tissues in which they are co-expressed.

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Partial deficiency of Thyroid transcription factor 1 produces predominantly neurological defects in humans and mice

Cited by 168 publications

References 25 publications

Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes

Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo

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