Connexin45 (GJC1) loss-of-function mutation contributes to familial atrial fibrillation and conduction disease
| Autor: | Willy G. Ye, Yan-Jie Li, Yi-Qing Yang, Honghong Chen, Ying-Jia Xu, Xing-Biao Qiu, Ruo-Gu Li, Donglin Bai |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Heterozygote medicine.medical_specialty Adolescent Sinus bradycardia DNA Mutational Analysis 030204 cardiovascular system & hematology Connexins Electrocardiography Young Adult 03 medical and health sciences 0302 clinical medicine Cardiac Conduction System Disease Heart Conduction System Genetic linkage Physiology (medical) Internal medicine Atrial Fibrillation Humans Medicine 030212 general & internal medicine Child Aged business.industry Cardiac arrhythmia Atrial fibrillation DNA Middle Aged medicine.disease Pedigree 3. Good health Heart failure Mutation Mutation (genetic algorithm) Cardiology Female medicine.symptom Cardiology and Cardiovascular Medicine business Atrioventricular block Familial atrial fibrillation |
| Zdroj: | Heart Rhythm. 18:684-693 |
| ISSN: | 1547-5271 |
| Popis: | Background Atrial fibrillation (AF) represents the most common clinical cardiac arrhythmia and substantially increases the risk of cerebral stroke, heart failure, and death. Although causative genes for AF have been identified, the genetic determinants for AF remain largely unclear. Objective This study aimed to investigate the molecular basis of AF in a Chinese kindred. Methods A 4-generation family with autosomal-dominant AF and other arrhythmias (atrioventricular block, sinus bradycardia, and premature ventricular contractions) was recruited. Genome-wide scan with microsatellite markers and linkage analysis as well as whole-exome sequencing analysis were performed. Electrophysiological characteristics and subcellular localization of the AF-linked mutant were analyzed using dual whole-cell patch clamps and confocal microscopy, respectively. Results A novel genetic locus for AF was mapped to chromosome 17q21.3, a 3.23-cM interval between markers D17S951 and D17S931, with a maximum 2-point logarithm of odds score of 4.2144 at marker D17S1868. Sequencing analysis revealed a heterozygous mutation in the mapping region, NM_005497.4:c.703A>T;p.(M235L), in the GJC1 gene encoding connexin45 (Cx45). The mutation cosegregated with AF in the family and was absent in 632 control individuals. The mutation decreased the coupling conductance in cell pairs (M235L/M235L, M235L/Cx45, M235L/Cx43, and M235L/Cx40), likely because of impaired subcellular localization. Conclusion This study defines a novel genetic locus for AF on chromosome 17q21.3 and reveals a loss-of-function mutation in GJC1 (Cx45) contributing to AF and other cardiac arrhythmias. |
| Databáze: | OpenAIRE |
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