Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction

Ishikawa, Taisuke; Ohno, Seiko; Murakami, Takashi; Yoshida, Kentaro; Mishima, Hiroyuki; Fukuoka, Tomoki; Kimoto, Hiroki; Sakamoto, Risa; Ohkusa, Takafumi; Aiba, Takeshi; Nogami, Akihiko; Sumitomo, Naokata; Shimizu, Wataru; Yoshiura, Koh-ichiro; Horigome, Hitoshi; Horie, Minoru; Makita, Naomasa

doi:10.1016/j.hrthm.2017.01.020

Cited by 46 publications

(28 citation statements)

References 24 publications

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“…Hyperpolarization activated cyclic nucleotide gated potassium channel 4 (HCN4) shows slow kinetics of activation and inactivation, and is necessary in cardiac pacemaking and conduction processes (Liang et al, 2015;Verkerk and Wilders, 2015). Abnormalities of HCN4 may result in a variety of arrhythmias, such as atrial fibrillation, sick sinus syndrome (DiFrancesco, 2015;Ishikawa et al, 2017). Increased HCN4 expression was reported in failing hearts in previous studies, which was consistent with our results.…”

Section: Discussionsupporting

confidence: 92%

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Chen

Xue

et al. 2019

Front. Genet.

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Aim: Heart failure (HF) is the end stage of various cardiovascular diseases. However, the precise regulation of gene expression profiles and functional mechanisms of long non-coding RNAs (lncRNAs) in HF remain to be elucidated. The present study aimed to identify the differentially expressed profiles and interaction of messenger RNAs (mRNAs) and lncRNAs in pressure overload-induced HF.Methods: Male Sprague-Dawley rats were randomly divided into the HF group and the sham-operated group. HF was induced by the transverse aortic constriction (TAC) surgery. The cardiac expression profiles of mRNAs and lncRNAs in HF were investigated using the microarray. Bioinformatics analyses and co-expression network construction were performed from the RNA sequencing data.Results: The expression profiles of mRNAs and lncRNAs showed significant differences between HF and controls. A total of 147 mRNAs and 162 lncRNAs were identified to be differentially expressed with a fold change of >2 in HF. The relative expression levels of several selected mRNAs and lncRNAs were validated by quantitative PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that diverse pathways were involved in the molecular mechanisms of cardiac hypertrophy and HF including immune response, smooth muscle contraction, ion transmembrane transport. The mRNA-lncRNA and transcription factors (TFs)-lncRNA co-expression networks were constructed and several genes and TFs were identified as key regulators in the pathogenesis of HF. Further functional prediction showed that the lncRNA NONRATT013999 was predicted to cis-regulate mRNA CDH11, and NONRATT027756 was predicted to trans-regulate HCN4.Conclusion: This study revealed specific expression regulation and potential functions of mRNAs and lncRNAs in pressure overload-induced HF. These results will provide new insights into the underlying mechanisms and potential therapeutic targets for HF.

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Section: Discussionsupporting

confidence: 92%

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Chen

Xue

et al. 2019

Front. Genet.

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“…We studied 88 articles, including 99 variants and 34 genes, after searching the PubMed database and identified 13 high-priority genes causing familial bradycardia, as follows: ABCC9 [18], ACTN2 [19], CACNA1C [20,21], DES [22][23][24][25][26][27], HCN4 [28][29][30][31][32], KCNQ1 [33,34], KCNH2 [35], LMNA [36,37], MECP2 [38], LAMP2 [39], NPPA [40], SCN5A [41][42][43][44][45], and TRPM4 [5,[46][47][48] (Table 3).…”

Section: Resultsmentioning

confidence: 99%

Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification Framework

Cheng

Zhao

et al. 2020

International Journal of Genomics

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Purpose. Next-generation sequencing (NGS) has become more accessible, leading to an increasing number of genetic studies of familial bradycardia being reported. However, most of the variants lack full evaluation. The relationship between genetic factors and bradycardia should be summarized and reevaluated. Methods. We summarized genetic studies published in the PubMed database from 2008/1/1 to 2019/9/1 and used the ACMG/AMP classification framework to analyze related sequence variants. Results. We identified 88 articles, 99 sequence variants, and 34 genes after searching the PubMed database and classified ABCC9, ACTN2, CACNA1C, DES, HCN4, KCNQ1, KCNH2, LMNA, MECP2, LAMP2, NPPA, SCN5A, and TRPM4 as high-priority genes causing familial bradycardia. Most mutated genes have been reported as having multiple clinical manifestations. Conclusions. For patients with familial CCD, 13 high-priority genes are recommended for evaluation. For genetic studies, variants should be carefully evaluated using the ACMG/AMP variant classification framework before publication.

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“…Therefore, we proposed it might be a novel ASD-associated gene. HCN4 is a hyperpolarization-activated cyclic nucleotide gated channel 4 expressed predominantly in heart ventricle, atrium, and neurons and has been reported being associated with Sick Sinus Syndrome and cardiac abnormalities (Ishikawa et al, 2017;Milano et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Refining critical regions in 15q24 microdeletion syndrome pertaining to autism

Liu

Zhang

Zarrei

et al. 2020

American J of Med Genetics Pt B

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Chromosome 15q24 microdeletion syndrome is characterized by developmental delay, facial dysmorphism, hearing loss, hypotonia, recurrent infection, and other congenital malformations including microcephaly, scoliosis, joint laxity, digital anomalies, as well as sometimes having autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we report a boy with a 2.58-Mb de novo deletion at chromosome 15q24. He is diagnosed with ASD and having multiple phenotypes similar to those reported in cases having 15q24 microdeletion syndrome. To delineate the critical genes and region that might be responsible for these phenotypes, we reviewed all previously published cases. We observe a potential minimum critical region of 650 kb (LCR15q24A-B) affecting NEO1 among other genes that might pertinent to individuals with ASD carrying this deletion. In contrast, a previously defined minimum critical region downstream of the 650-kb interval (LCR15q24B-D) is more likely associated with the developmental delay, facial dysmorphism, recurrent infection, and other congenital malformations. As a result, the ASD phenotype in this individual is potentially attributed by genes particularly NEO1 within the newly proposed critical region. K E Y W O R D S15q24 microdeletion, autism spectrum disorder, critical region, de novo

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Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction

Cited by 46 publications

References 24 publications

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification Framework

Refining critical regions in 15q24 microdeletion syndrome pertaining to autism

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