Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency

Krude, Heiko; Schütz, Barbara; Biebermann, Heike; Moers, Arpad von; Schnabel, Dirk; Neitzel, Heidi; Tönnies, Holger; Weise, Dagmar; Lafferty, Antony; Schwarz, S.; DeFelice, Mario; Deimling, Andreas von; Landeghem, Frank K.H. van; DiLauro, Roberto; Grüters, Annette

doi:10.1172/jci0214341

Cited by 285 publications

(171 citation statements)

References 28 publications

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“…This is predicted to cause haploinsufficiency, either as a result of a non-functional, truncated NKX2-1 protein or 50% reduction of the protein levels due to NMD degradation of the premature termination codon containing NKX2-1 mRNA allele. [6,7] While BHC, with its characteristic choreiform movements, would not commonly be confused with ataxic CP, similar cases have been reported [11,12]. Doyle et al 12 reported siblings with an NKX2-1 mutation who had congenital hypothyroidism, global developmental delay and later ataxia, choreoathetosis and dysarthria.…”

Section: Discussionmentioning

confidence: 86%

“…[4] Deletions, missense mutations and nonsense mutations have been described in NKX2-1 and result in haploinsufficiency. [6,7] The gene is highly expressed in the fetal brain and is involved in neuronal migration and development of the basal ganglia. [8] We report a father and his two children who were diagnosed with ataxic CP in early childhood.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy

McMichael

Haan

Gardner

et al. 2013

European Journal of Medical Genetics

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy

McMichael

Haan

Gardner

et al. 2013

European Journal of Medical Genetics

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“…Nevertheless, there might still be a risk that CH with delayed onset due to thyroid hypoplasia is undiagnosed by neonatal screening. It is also evident that despite optimal treatment a subset of children with CH never develops normally due to the fact that the missing factor(s) of importance for normal thyroid organogenesis is required for the embryonic development of the brain and other organs independently of thyroid hormone (Krude et al, 2002). Moreover, congenital heart disease is overrepresented among children with thyroid dysgenesis, suggesting a developmental relationship between the thyroid and the cardiovascular system (Olivieri et al, 2002).…”

Section: Congenital Hypothyroidismmentioning

confidence: 99%

“…In humans Nkx2-1 haploinsufficiency gives rise to a syndrome characterized by thyroid hypoplasia, choreoathetosis and pulmonary disease (Krude et al, 2002;Pohlenz et al, 2002). The neurological symptoms cannot be rescued by thyroxin, illustrating the importance of Nkx2-1 transcriptional activity in forebrain development.…”

Section: Nkx2-1mentioning

confidence: 99%

Morphogenesis of the thyroid gland

Fagman

Nilsson

2010

Molecular and Cellular Endocrinology

130

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Congenital hypothyroidism is mainly due to structural defects of the thyroid gland, collectively known as thyroid dysgenesis. The two most prevalent forms of this condition are abnormal localization of differentiated thyroid tissue (thyroid ectopia) and total absence of the gland (athyreosis). The clinical picture of thyroid dysgenesis suggests that impaired specification, proliferation and survival of thyroid precursor cells and loss of concerted movement of these cells in a distinct spatiotemporal pattern are major causes of malformation. In normal development the thyroid primordium is first distinguished as a thickening of the anterior foregut endoderm at the base of the prospective tongue. Subsequently, this group of progenitors detaches from the endoderm, moves caudally and ultimately differentiates into hormone-producing units, the thyroid follicles, at a distant location from the site of specification. In higher vertebrates later stages of thyroid morphogenesis are characterized by shape remodelling into a bilobed organ and the integration of a second type of progenitors derived from the caudal-most pharyngeal pouches that will differentiate into C-cells. The present knowledge of thyroid developmental dynamics has emerged from embryonic studies mainly in chicken, mouse and more recently also in zebrafish. This review will highlight the key morphogenetic steps of thyroid organogenesis and pinpoint which crucial regulatory mechanisms are yet to be uncovered. Considering the coincidence of thyroid dysgenesis and congenital heart malformations the possible interactions between thyroid and cardiovascular development will also be discussed.

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“…Loss of Nkx2.5 in mice results in embryonic demise at E9.5 resulting from aberrant cardiac development with defects in looping morphogenesis and ventricular specification (Lyons et al, 1995). Dominant mutations in NKX2.1 and NKX2.5 in humans lead to congenital pulmonary and cardiac defects, respectively, demonstrating their importance in adult tissue homeostasis (Krude et al, 2002;Schott et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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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Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency

Cited by 285 publications

References 28 publications

NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy

NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy

Morphogenesis of the thyroid gland

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

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