Connexin 43 remodeling induced by LMNA gene mutation Glu82Lys in familial dilated cardiomyopathy with atrial ventricular block.
BACKGROUND
Mutations in the lamin A/C gene (LMNA) may cause familial dilated cardiomyopathy (dilated cardiomyopathy) characterized by early onset atrio-ventricular block (A-V block) before the manifestation of dilated cardiomyopathy and high risk of sudden death due to ventricular arrhythmia, which is very similar to the phenotype of gap junction related heart disease. This study aimed to determine the expression and localization of connexins in neonatal myocytes transfected with wild-type (WT) or mutant LMNA to elucidate how these mutations cause heart diseases.


METHODS
We studied the connexin 43 (Cx43) and connexin 40 (Cx40) expression in cultured neonatal myocytes transfected with wild-type (WT) or mutant LMNA (Glu82Lys (E82K) and Arg644Cys (R644C)) using confocal imaging and Western blotting analysis.


RESULTS
Cx43 protein expression was reduced by 40% in cells transfected with LMNA E82K than that in cells transfected with WT LMNA cDNA. Confocal imaging showed that the Cx43 located inside the cells by LMNA E82K. By contrast, LMNA E82K mutation had no effect on expression and localization of Cx40. LMNA R644C transfection did not show any significant effects on gap junctions at all.


CONCLUSIONS
Our findings suggest that LMNA E82K significantly reduced the Cx43 expression and altered its localization which may be one of the pathological mechanisms underlying LMNA-related heart disease.
Sun
Li-ping
LP
Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Wang
Lin
L
Wang
Hui
H
Zhang
Yin-hui
YH
Pu
Jie-lin
JL
D000818:Animals; D001283:Atrioventricular Node / Q000473:pathology; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D051381:Rats; D014162:Transfection; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D034904:Lamin Type A; D000097003:Gap Junction alpha-5 Protein