Novel Point Mutation in the Cardiac Transcription Factor CSX/NKX2.5 Associated With Congenital Heart Disease.

Ikeda, Yuichi; Hiroi, Yukio; Hosoda, Toru; Utsunomiya, Toshinori; Matsuo, Shuzo; Ito, Tsuyoshi; Inoue, Junya; Sumiyoshi, Tetsuya; Takano, Hiroyuki; Nagai, Ryozo; Komuro, Issei

doi:10.1253/circj.66.561

Cited by 84 publications

(44 citation statements)

References 20 publications

(14 reference statements)

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“…The knock-in of the GFP reporter gene into one of the Nkx2.5 loci may influence the developmental changes of Nkx2.5/GFP(+) cardiac precursor cells, suggested by the association of Nkx2.5 dysfunction with the congenital heart disease. 10 However, we conclude that half of the dose of Nkx2.5 is sufficient to induce both cardiac differentiation (as described elsewhere 5 ) and the developmental changes of Ni 2+ sensitivity and automaticity in Nkx2.5/GFP(+) cells, because we had similar results from cardiac precursor cells derived from another ES cell line with intact Nkx2.5 function (data not shown).…”

supporting

confidence: 68%

“…ES-cell-derived cardiac precursor cells were purified from the EBs using GFP as a reporter as described by Hidaka et al 5 Action potentials and T-type Ca 2+ currents from the Nkx2.5/GFP(+) cells were recorded using perforated patch-clamp and standard voltage-clamp techniques. 6,7 The effects of various drugs on the automaticity of Nkx2.5/GFP(+) cells were tested in the early (≤8 after differentiation), intermediate (days [9][10][11][12][13][14][15][16][17][18][19] and late stages (≥day 20) of differentiation as described by …”

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confidence: 99%

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Developmental Changes of Ni2+ Sensitivity and Automaticity in Nkx2.5-Positive Cardiac Precursor Cells From Murine Embryonic Stem Cell

Manabe

Miake

Sasaki

et al. 2004

Circ J

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confidence: 68%

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confidence: 99%

Developmental Changes of Ni2+ Sensitivity and Automaticity in Nkx2.5-Positive Cardiac Precursor Cells From Murine Embryonic Stem Cell

Manabe

Miake

Sasaki

et al. 2004

Circ J

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“…None of these factors are expressed by the thyroid progenitor cells implicating that they act non-cell-autonomously. However, deletion of Nkx2.5, a homeobox transcription factor previously shown to be expressed in both the embryonic heart and the thyroid primordium (Lints et al, 1993), leads to developmental defects in both organs (Ikeda et al, 2002;Dentice et al, 2006). As Nkx2.5 is transcriptionally regulated by Isl1 in cardiac progenitors (Takeuchi et al, 2005), it is tempting to speculate that the same might account for Nkx2.5 in the thyroid bud.…”

Section: Discussionmentioning

confidence: 99%

Expression of Islet1 in thyroid development related to budding, migration, and fusion of primordia

Westerlund¹,

Andersson²,

Carlsson³

et al. 2008

Developmental Dynamics

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The LIM homeodomain transcription factor Isl1 was investigated in mouse thyroid organogenesis. All progenitor cells of the midline thyroid diverticulum and lateral primordia (ultimobranchial bodies) expressed Isl1. This pattern persisted until the growing anlagen fused at embryonic day (E) 13.5. In Isl1 null mutants thyroid progenitors expressing Nkx2.1 and Pax8 were readily specified in the anterior endoderm but the size of the thyroid rudiment was reduced. In late development, only immature C-cells expressed Isl1. In the adult gland the number of Isl1؉ cells was small compared with cells expressing calcitonin. Analysis of microarray profiles indicated a higher level of Isl1 expression in medullary thyroid carcinomas than in tumors derived from follicular cells. Together, these findings suggest that Isl1 may be a novel regulator of thyroid development before terminal differentiation of the endocrine cell types. Isl1 is an embryonic C-cell precursor marker that may be relevant also in cancer developed from the mature C-cell. Developmental Dynamics 237:3820 -3829, 2008.

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“…Eleven truncating mutations have previously been reported, 1,4,6,7,11,15 including a deletion of amino acids 198 -324 (called M198), which occurs carboxy-terminal to the homeodomain, and overlaps with the region deleted in AC-80. The M198 protein showed normal binding and transactivation of a ANF-luciferase reporter, but a decreased ability to form dimers.…”

Section: Discussionmentioning

confidence: 99%

A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype?

et al. 2006

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The prevalence of congenital heart defects is approximately 1% of all live births. Identifying the genes responsible for cardiac malformation is the first step to understand pathogenesis. Heterozygous mutations in the CSX/NKX2-5 (NKX2E) gene have been identified to cause atrial septal defect (ASD) and/or atrioventricular (AV) conduction disturbance in some families. However, there is great variability in expressivity of the phenotype between the patients with a CSX/NKX2-5 mutation. We screened four sporadic patients and three index cases of families with ASD and/or conduction defects. In one of them, a CSX/NKX2-5 mutation was identified. This novel mutation (p.Tyr256X) was inherited in a three-generation family causing five individuals to have cardiac anomalies ranging from ASD to arrhythmias. Interestingly, all the observed AV conduction disturbances were at the nodal level, manifesting first as an AV block of the first degree and evolving toward a second-degree block. Atrial fibrillation, previously reported in three individuals with CSX/NKX2-5 mutations, was observed in three patients.

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Novel Point Mutation in the Cardiac Transcription Factor CSX/NKX2.5 Associated With Congenital Heart Disease.

Cited by 84 publications

References 20 publications

Developmental Changes of Ni2+ Sensitivity and Automaticity in Nkx2.5-Positive Cardiac Precursor Cells From Murine Embryonic Stem Cell

Developmental Changes of Ni2+ Sensitivity and Automaticity in Nkx2.5-Positive Cardiac Precursor Cells From Murine Embryonic Stem Cell

Expression of Islet1 in thyroid development related to budding, migration, and fusion of primordia

A novel CSX/NKX2-5 mutation causes autosomal-dominant AV block: are atrial fibrillation and syncopes part of the phenotype?

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