Gap junction protein beta 4 plays an important role in cardiac function in humans, rodents, and zebrafish

Autor: Masaaki Ito, Issei Kobayashi, Kaoru Dohi, Yusuf Ali, Rie Ito, Yoshiki Sawa, Yoshinori Yoshida, Toshio Tanaka, Shunsuke Saito, Ryuji Okamoto, Ryotaro Hashizume, Misato Nishikawa, Itaru Goto, Yuhei Nishimura, Yuhko Kobayashi
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Pathology
DNA Mutational Analysis
Myocardial Infarction
Cardiovascular Medicine
Gene mutation
Connexins
Muscle hypertrophy
Mice
Medical Conditions
0302 clinical medicine
Animal Cells
Medicine
Child
Cardiomyocytes
Stem Cells
Eukaryota
Gap Junctions
Heart
Pedigree
Osteichthyes
Cardiovascular Diseases
COS Cells
Junctional Complexes
Cellular Types
Cardiomyopathies
Cardiac function curve
Cell Physiology
medicine.medical_specialty
Science
Induced Pluripotent Stem Cells
Primary Cell Culture
Neurophysiology
03 medical and health sciences
Protein Domains
Humans
Genetic Testing
Myocardium
Organisms
Biology and Life Sciences
medicine.disease
Fish
Biological Tissue
030104 developmental biology
Connexin 43
Synapses
Animal Studies
Neuroscience
0301 basic medicine
Physiology
Cardiomyopathy
Connexin
030204 cardiovascular system & hematology
Nervous System
Animals
Genetically Modified
Gene Knockout Techniques
Chlorocebus aethiops
Medicine and Health Sciences
Myocytes
Cardiac
Zebrafish
Multidisciplinary
biology
Angiotensin II
Hypertrophic cardiomyopathy
Cardiac muscle
Animal Models
Electrophysiology
medicine.anatomical_structure
Experimental Organism Systems
Vertebrates
Female
Anatomy
Research Article
Adult
Cardiac Ventricles
Cardiology
Muscle Tissue
Mouse Models
Research and Analysis Methods
Model Organisms
Cardiomyopathy
Hypertrophic
Familial
Animals
Muscle Cells
business.industry
Cell Biology
Zebrafish Proteins
biology.organism_classification
Rats
Disease Models
Animal
Amino Acid Substitution
Doxorubicin
Cardiovascular Anatomy
Heart Transplantation
business
Zoology
Zdroj: PLoS ONE, Vol 15, Iss 10, p e0240129 (2020)
PLoS ONE
ISSN: 1932-6203
Popis: AimsGJB4 encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. This study investigated whether GJB4 plays an important role in human heart disease and function.Methods and resultsWe examined a patient and her older brother who both presented with complicated severe hypertrophic cardiomyopathy (HCM) and whose parents are healthy married cousins. The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid changes for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations, the gene for GJB4 was the only identified gene that is possibly associated with cardiac muscle. The resultant E204A substitution exists in the 4th transmembrane domain. GJB4-E204A impaired the binding with gap junction protein A1 (GJA1) compared with GJB4-WT. The expression of GJB4 was induced in rat disease models of left and right ventricle hypertrophy and mouse disease models of adriamycin-induced cardiomyopathy and myocardial infarction, while it was not detected at all in control. An immunohistochemical study was performed for autopsied human hearts and the explanted heart of the patient. GJB4 was expressed and colocalized with GJA1 in intercalated discs in human diseased hearts, which was extensively enhanced in the explanted heart of the patient. The abnormal expression and localization of GJB4 were observed in beating spheres of patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). We generated knockout zebrafish of GJB4 by CRISPR/Cas9 and the endodiastolic volume and the ventricular ejection fraction were significantly lower in GJB4-deficient than in wild-type zebrafish at five days post-fertilization.ConclusionsThese results indicate both that GJB4 is defined as a new connexin in diseased hearts, of which mutation can cause a familial form of HCM, and that GJB4 may be a new target for the treatment of cardiac hypertrophy and dysfunction.
Databáze: OpenAIRE
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