Identification and functional characterization of KLF5 as a novel disease gene responsible for familial dilated cardiomyopathy

Di, Ruo-Min; Yang, Chenxi; Zhao, Cuimei; Fang, Yuan; Qiao, Qi; Gu, Jun; Li, Xiumei; Xu, Ying‐Jia; Yang, Yi‐Qing

doi:10.1016/j.ejmg.2019.103827

Cited by 18 publications

(15 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a member of the Krüppel-like factors (KLFs) family, KLF5 is intimately correlated with cardiovascular remodeling, cardiac energetic, and cardiac fibroblasts [52][53][54][55]. Notably, KLF5 has recently been proved as a novel disease gene of familial dilated cardiomyopathy (DCM) and negatively regulates HCM [56,57]. MAFK, a member of the small Maf family, is an important contributor to hematopoiesis [58].…”

Section: Discussionmentioning

confidence: 99%

Immune-Related Genes: Potential Regulators and Drug Therapeutic Targets in Hypertrophic Cardiomyopathy

Liu

Cai

et al. 2021

Journal of Nanomaterials

View full text Add to dashboard Cite

Background. Accumulating evidence shows that the innate immune system is a key player in cardiovascular repair and regeneration, but little is known about the role of immune-related genes (IRGs) in hypertrophic cardiomyopathy (HCM). Methods. The differential mRNA expression profiles of HCM samples were downloaded from the Gene Expression Omnibus (GEO) dataset (GSE89714), and the IRG expression profile was obtained from the ImmPort database. The regulatory pathways of IRGs in HCM were screened out through discrepantly expressive genes (DEGs) analysis, enrichment of gene function/pathway analysis, and protein-protein interaction (PPI) network. Besides, hub IRGs in the PPI network were selected for drug prediction. Results. A total of 854 genes were differentially expressed in HCM, of which 88 were IRGs. Functional enrichment analysis revealed that 88 IRGs were mainly involved in the biological processes (BP) of SMAD protein pathway, smooth muscle cell proliferation, protein serine/threonine kinase, and mitogen-activated protein kinase (MAPK) cascade. Cytokine-cytokine receptor interaction, TGFβ signaling pathway, PI3K-Akt signaling pathway, and MAPK signaling pathway were enriched in the pathway enrichment analysis of these 88 IRGs. Furthermore, the PPI regulatory network of IRGs was constructed, and 10 hub IRGs were screened out to construct a regulatory network for HCM. 4 transcription factors (TFs) were the major regulator of 10 hub IRGs. Finally, these 10 hub IRGs were entered into the pharmacogenomics database for prediction, and the relevant drugs were obtained. Conclusions. In this study, 10 hub IRGs were coexpressed with 4 TFs to construct a regulatory network for HCM. Drug prediction of these 10 hub IRGs proposed potential therapeutic agents that could be used in HCM. These results indicate that IRGs are potential regulators and drug therapeutic targets in HCM.

show abstract

Section: Discussionmentioning

confidence: 99%

Immune-Related Genes: Potential Regulators and Drug Therapeutic Targets in Hypertrophic Cardiomyopathy

Liu

Cai

et al. 2021

Journal of Nanomaterials

View full text Add to dashboard Cite

show abstract

“…Whole-exome sequencing (WES) was performed as previously described. 50,51) Briefly, each exome library was constructed using 3 μg of genomic DNA and captured using the SureSelect XT Human All Exon V6 Kit (Agilent Technologies, Santa Clara, CA, USA) according to the manufacturer's protocol. The constructed exome libraries were enriched and sequenced on the Illumina HiSeq 2000 Genome Analyzer (Illumina, San Diego, CA, USA) using the HiSeq Sequencing Kit (Illumina) according to the manufacturer's analysis of the WES data was conducted as described elsewhere.…”

Section: Study Subjectsmentioning

confidence: 99%

“…The constructed exome libraries were enriched and sequenced on the Illumina HiSeq 2000 Genome Analyzer (Illumina, San Diego, CA, USA) using the HiSeq Sequencing Kit (Illumina) according to the manufacturer's analysis of the WES data was conducted as described elsewhere. 50,51) The minor allele frequency for each genetic variant was calculated according to such population genetic databases as the NHLBI Exome Sequencing Project database (https://ev s.gs.washington.edu/EVS/), the Single Nucleotide Polymorphism database (https://www.ncbi.nlm.nih.gov/snp/), and the Genome Aggregation Database (https://gnomad.br oadinstitute.org/). The disease-causing potential of a novel genetic variation was predicted using PolyPhen-2 (http://g enetics.bwh.harvard.edu/pph2), MutationTaster (http://ww w.mutationtaster.org), SIFT (http://sift.jcvi.org/www/SIFT_ enst_submit.html), and PROVEAN (http://provean.jcvi.org/ index.php).…”

Section: Study Subjectsmentioning

confidence: 99%

“…54,55) Cell transfection and dual-luciferase assay: COS-7 and 293T cells were cultivated and transiently transfected with various plasmids using the Lipofectamine 3000 reagent (Invitrogen) as described previously. 50,51) The pGL4.75 plasmid (Promega), which expresses the Renilla luciferase, was used as an internal control to normalize the transfection efficiency. In brief, COS-7 cells were transfected with 400 ng of empty pcDNA3.1, 400 ng of wild-type SOX17-pcDNA3.1, 400 ng of Gln127*-mutant SOX-pcDNA3.1, 200 ng of wild-type SOX-pcDNA3.1 plus 200 ng of empty pcDNA3.1, or 200 ng of wild-type SOX17-pcDNA 3.1 plus 200 ng of Gln127*-mutant SOX-pcDNA3.1, together with 1000 ng of NOTCH1-luc and 25 ng of pGL 4.75.…”

Section: Study Subjectsmentioning

confidence: 99%

See 1 more Smart Citation

SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension

Wang

et al. 2021

Int. Heart J.

Self Cite

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM _022454.4: c.379C>T; p.(Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode β-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.

show abstract

“…were identified in large DCM pedigrees (Table 1). 5 Studies evaluating Chinese families have recently reported several novel genes and variations associated with DCM, including MEF2C , HAND2 , ZBTB17 , ISL1 , KLF5 , CASZ1 , etc 6–10 . Basic studies have been conducted based on novel gene reporting to deepen our understanding of the pathogenesis of DCM.…”

Section: Dilated Cardiomyopathymentioning

confidence: 99%

Cardiomyopathies in China: A 2018–2019 state‐of‐the‐art review

Hua

Zhang

2020

Chronic Diseases and Translational Medicine

View full text Add to dashboard Cite

Cardiomyopathies are diseases of the cardiac muscle and are often characterized by ventricular dilation, hypertrophy, and cardiac arrhythmia. Patients with cardiomyopathies often experience sudden death and cardiac failure and require cardiac transplantation during the course of disease progression. Early diagnosis, differential diagnosis, and genetic consultation depend on imaging techniques, genetic testing, and new emerging diagnostic tools such as serum biomarkers. The molecular genetics of cardiomyopathies has been widely studied recently. The discovery of mechanisms underlying heterogeneity and overlapping of the phenotypes of cardiomyopathies has revealed the existence of disease modifiers, and this has led to the emergence of novel disease-modifying therapy. This 2018–2019 state-of-the-art review outlines the pathogenesis, diagnosis, and treatment of cardiomyopathies in China.

show abstract

Identification and functional characterization of KLF5 as a novel disease gene responsible for familial dilated cardiomyopathy

Cited by 18 publications

References 47 publications

Immune-Related Genes: Potential Regulators and Drug Therapeutic Targets in Hypertrophic Cardiomyopathy

Immune-Related Genes: Potential Regulators and Drug Therapeutic Targets in Hypertrophic Cardiomyopathy

SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension

Cardiomyopathies in China: A 2018–2019 state‐of‐the‐art review

Contact Info

Product

Resources

About