Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein

Kasahara, Hideko; Wakimoto, Hiroko; Liu, Margaret; Maguire, Colin T.; Converso, Kimber; Shioi, Tetsuo; Huang, Weei‐Yuarn; Manning, Warren J.; Paul, David L.; Lawitts, Joel; Berul, Charles I.; Izumo, Seigo

doi:10.1172/jci12694

Cited by 124 publications

(79 citation statements)

References 45 publications

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“…In particular, a transiently elevated expression of NKX2-5 was observed in specialized myocardial conduction cells during the development of cardiac conduction system (Akazawa and Komuro, 2005). In transgenic mice expressing a DNA binding-impaired mutant of mouse NKX2-5 (I183P), under the β-myosin heavy chain promoter, the accumulation of mutant protein in the embryo, neonate, and adult myocardium resulted in progressive and profound cardiac conduction defects and heart failure (Kasahara et al, 2001). 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).…”

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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“…Recently, it has been shown that the transcriptional up-regulation of Cx43 by RasRaf-MAPK is mediated by the interaction of a novel Cx43 promoter element with a protein complex that contains both HSP90 and c-Myc (51). Overexpression of Nkx2.5, a member of the NK2 homeodomain proteins was associated with a decrease in Cx43 expression, suggesting that Nkx2.5 may function as a transcriptional repressor (52). SP1 has also been found involved in the transcriptional regulation of Cx26, in rat mammary gland and uterus, as well as in the activation of Cx40 and Cx32 proximal promoter (53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Critical Role of the Transcriptional Repressor Neuron-restrictive Silencer Factor in the Specific Control of Connexin36 in Insulin-producing Cell Lines

Martín

Tawadros

Meylan

et al. 2003

Journal of Biological Chemistry

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Adjacent cells share ions, second messengers, small metabolites, and signaling molecules with a weight as high as 1000 Da (1) through intercellular channels that form gap junctions. This type of intercellular communication permits coordinated cellular activity and allows cells to review the functional state of their neighbors, a critical feature for the homeostasis of multicellular organisms (1-4). Intercellular channels result from the association of two half-channels named connexons, which are contributed to separately by each of two adjacent cells. Each connexon is an assembly of membrane proteins named connexins, which are encoded by a gene family consisting of at least 20 members (5, 6).It has been reported that Cx36 1 is the predominantly expressed connexin in rodent neuronal cells (7-9). Immunogold labeling using freeze-fracture replicas have shown that Cx36 was found only in neurons (10) and indicate that the specific expression of connexins by the different cell types of the nervous system may define separate pathways for neuronal versus glial gap junction communication (10 -12). We recently found that Cx36 is the predominant if not the sole connexin isoform expressed in insulin-producing ␤-cells of rat and mouse pancreatic islets (13,14). Recently, Cx36 content was modified in insulin-secreting cells by using an adenoviral gene transfer approach (15) or a lentivirus-mediated transduction of cx36 cDNA (16) in order to evaluate the contribution of Cx36 in the control of insulin secretion and content. These experiments have demonstrated that tight levels of Cx36 are crucial for proper function of insulin-producing cells. Moreover, stably transfected insulin-secreting MIN6 cells with a cx36 antisense cDNA impaired the synchronization of glucose-induced Ca( 2ϩ ) oscillations and insulin secretion in response to glucose (17). These data provided evidence that proper storage of insulin as well as the regulation of insulin release required that the levels of Cx36 be maintained within native values.The objective of the present study was to characterize the mechanisms of cell-specific expression of Cx36. The presence of several gene transcripts in pancreatic ␤-cells and neuronal cells was correlated with the absence in these cell types of a transcription factor named NRSF/REST (neuron-restrictive silencer factor/repressor element silencing transcription factor) (18). NRSF/REST binds to a 21-bp cis element named neuronal restrictive silencer element (NRSE). Through this NRSE, NRSF/REST has been identified as a negative regulatory system that silences neuronal gene expression in non-neuronal tissues, neuronal precursor cells, and certain differentiated

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“…45,46) In contrast, heart-restricted expression of a dominant-negative human NKX2-5 mutant in the mouse induced progressive atrioventricular conduction defects and heart failure, and injection of doxorubicin promoted more severe cardiac dysfunction and increased cardiomyocyte apoptosis. 47,48) Moreover, NKX2-5 has been demonstrated to promote cardiomyocyte differentiation and mediate adult cardiac hypertrophic response through interacting with other important cardiac transcription factors, such as TBX5, GATA4 and SRF. [49][50][51] Furthermore, NKX2-5 also regulates expression of gap junction protein connexin43 and sarcomere organization in postnatal cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

“…[49][50][51] Furthermore, NKX2-5 also regulates expression of gap junction protein connexin43 and sarcomere organization in postnatal cardiomyocytes. 47) In humans, an increasing number of NKX2-5 mutations have been associated with various congenital heart diseases including ASD, ventricular septal defect, Fallot's tetralogy, hypoplastic left ventricle transposition of the great arteries and valvular deformities, cardiac arrhythmias including cardiac conduction block and atrial fibrillation, and DCM. 32,33,52) Collectively, these findings along with the present study indicate that NKX2-5 plays important roles not only in early cardiovascular morphogenesis, but also in the postnatal maturation and homeostasis of cardiomyocytes and the adaptive remodeling of adult heart.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

Guo

et al. 2017

Int. Heart J.

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SummaryDilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients. (Int Heart J 2017; 58: 521-529)

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Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein

Cited by 124 publications

References 45 publications

Novel NKX2-5 mutations responsible for congenital heart disease

Novel NKX2-5 mutations responsible for congenital heart disease

Critical Role of the Transcriptional Repressor Neuron-restrictive Silencer Factor in the Specific Control of Connexin36 in Insulin-producing Cell Lines

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

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