Cardiac Septal and Valvular Dysmorphogenesis in Mice Heterozygous for Mutations in the Homeobox Gene
            <i>Nkx2-5</i>

Biben, Christine; Weber, Roberta K.; Kesteven, Scott; Stanley, Edouard G.; McDonald, Lachlan; Elliott, David A.; Barnett, Louise; Köentgen, Frank; Robb, Lorraine; Feneley, Michael P.; Harvey, Richard P.

doi:10.1161/01.res.87.10.888

Cited by 314 publications

(246 citation statements)

References 23 publications

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“…Targeted disruption of NKX2-5 in mice caused embryonic lethality around ED10.5, with retarded cardiac development (Lyons et al, 1995;Tanaka et al, 1999). Mice heterozygous for NKX2-5-null alleles were predisposed to atrial septal defect and abnormal atrioventricular conduction (Biben et al, 2000). Ventricular-restricted NKX2-5 knockout around ED8.0 to ED8.5, created by crossing floxed-NKX2-5 mice with myosin light chain 2v-Cre knock-in mice, gave rise to progressive and advanced conduction defects and left ventricular hypertrophy postnatally (Pashmforoush et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Novel NKX2-5 mutations responsible for congenital heart disease

Wang

Xy²,

Yq³

2011

Genet. Mol. Res.

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ABSTRACT. Congenital heart disease (CHD) is the most common birth defect and is the leading cause of infant morbidity and mortality resulting from birth defects. Increasing evidence demonstrates that genetic variation in the NKX2-5 gene, which encodes a homeobox-containing transcription factor crucial to cardiogenesis, is an important molecular determinant for CHD. Nevertheless, the genetic components underlying CHD remain largely unknown. We screened NKX2-5 for potential molecular defects in patients with CHD. The entire coding region of NKX2-5 was initially sequenced in a cohort of 268 unrelated patients with CHD. The relatives of the patients carrying identified mutations and 200 unrelated control individuals were subsequently genotyped. Three novel heterozygous missense NKX2-5 mutations, p.Q22K, p.R36S, and p.E54K, were identified in three families with autosomal dominantly inherited atrial septal defect, ventricular septal defect, and tetralogy of Fallot, respectively. These mutations, absent in 200 control individuals, appear to be highly conserved evolutionarily and co-segregated with CHD in the families, with complete penetrance. These findings expand the spectrum of mutations in NKX2-5 associated with CHD and provide new insight into the molecular etiology involved in the pathogenesis of CHD, which signifies potential implications for genetic diagnosis and gene-specific therapy for this common disease in newborns.

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Section: Discussionmentioning

confidence: 99%

Novel NKX2-5 mutations responsible for congenital heart disease

Wang

Xy²,

Yq³

2011

Genet. Mol. Res.

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“…18 Therefore, we repeated the same experiments using cardiac precursor cells from a different murine ES cell line with intact Nkx2.5 function (data not shown). We obtained similar results from these cells, excluding the effects of Nkx2.5 gene dosage or GFP gene expression on the developmental changes in Ni 2+ sensitivity of ICa,T.…”

Section: Effects Of Ni 2+ On Icat Of Nkx25/gfp(+) Cells In the Earlmentioning

confidence: 99%

Subtype Switching of T-Type Ca 2+ Channels From Cav3.2 to Cav3.1 During Differentiation of Embryonic Stem Cells to Cardiac Cell Lineage

Mizuta

Miake

Yano

et al. 2005

Circ J

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Background The developmental changes of Ni 2+ -sensitivity to automaticity of Nkx2.5-positive cells derived from mouse embryonic stem cell have been identified, suggesting developmental regulation of expressing Ni 2+ -sensitive T-type Ca 2+ channel, although the mechanism of the change has not been fully studied. Methods and Results Transcripts of Cav3.2, Cav3.1 and Cav1.2 genes of beating Nkx2.5-positive cells, which encode the Ni 2+ -sensitive T-type Ca 2+ channel, Ni 2+ -insensitive T-type Ca 2+ channel, and L-type Ca 2+ channel, respectively, were investigated by real-time reverse-transcriptase-polymerase chain reaction, and the current density of each channel was measured by patch-clamp techniques at the early and late stages of differentiation. The expression of the Cav3.2 transcript predominated in the early stage whereas those of Cav3.1 and Cav1.2 transcripts were upregulated in the late stage, which was consistent with the change in each current density, suggesting the expression of channel proteins is largely determined at the transcriptional level. ConclusionThe results indicate that the mechanism of change of Ni 2+ -sensitivity is partly, if not completely, the subtype switch of T-type Ca 2+ channel from Cav3.2 to Cav3.1 at the transcriptional level, and that the expression of the L-type Ca 2+ channel might have an attenuating effect on Ni 2+ -sensitivity to automaticity in the late stage of differentiation. (Circ J 2005; 69: 1284 -1289

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“…50 Based on studies in individual patients, linkage analysis in families and animal studies, several other genes and candidate loci have been implicated to be potentially involved in BAV. [51][52][53][54][55][56][57][58] These studies emphasize the genetic as well as phenotypic heterogeneity of BAV.…”

Section: Bicuspid Aortic Valve: Clinical and Genetic Aspectsmentioning

confidence: 99%

Clinical and Genetic Aspects of Bicuspid Aortic Valve: A Proposed Model for Family Screening Based on a Review of Literature

et al. 2015

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Bicuspid aortic valve (BAV) is the most common congenital cardiac defect causing serious morbidity including valvular dysfunction and thoracic aortic aneurysms (TAA) in around 30% of BAV patients. Cardiological screening of first-degree relatives is advised in recent guidelines given the observed familial clustering of BAV. However, guidelines regarding screening of family members and DNA testing are not unequivocal. The aim of this review is to provide an overview of the literature on echocardiographic screening in first-degree relatives of BAV patients and to propose a model for family screening. In addition, we provide a flowchart for DNA testing. We performed a PubMed search and included studies providing data on echocardiographic screening in asymptomatic relatives of BAV patients. Nine studies were included. In 5.8-47.4% of the families BAV was shown to be familial. Of the screened first-degree relatives 1.8-11% was found to be affected with BAV. Results regarding a potential risk of TAA in first-degree relatives with a tricuspid aortic valve (TAV) were conflicting. The reported familial clustering of BAV underlines the importance of cardiological screening in relatives. After reviewing the available family history, patient characteristics and the results of cardiological screening in relatives, follow-up in relatives with a TAV and/or DNA testing may be advised in a subset of families. In this study we propose a model for the clinical and genetic work-up in BAV families, based on the most extensive literature review on family screening performed until now.

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Cardiac Septal and Valvular Dysmorphogenesis in Mice Heterozygous for Mutations in the Homeobox Gene Nkx2-5

Cited by 314 publications

References 23 publications

Novel NKX2-5 mutations responsible for congenital heart disease

Novel NKX2-5 mutations responsible for congenital heart disease

Subtype Switching of T-Type Ca 2+ Channels From Cav3.2 to Cav3.1 During Differentiation of Embryonic Stem Cells to Cardiac Cell Lineage

Clinical and Genetic Aspects of Bicuspid Aortic Valve: A Proposed Model for Family Screening Based on a Review of Literature

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