A novel mutation in GPD1L associated with early repolarization syndrome via modulation of cardiomyocyte fast sodium currents.
Int J Mol Med
; 45(3): 947-955, 2020 Mar.
Article
em En
| MEDLINE
| ID: mdl-31922248
ABSTRACT
Early repolarization syndrome (ERS) is associated with genetic mutations, but the role of the glycerol3phosphate dehydrogenase 1like (GPD1L) mutation remains unclear. The aim of the present study was to investigate the role and potential underlying mechanism of GPD1L mutation P112L in the pathogenesis of ERS. Wholegenome sequencing was performed on samples from a family with ERS, and the gene sequencing results were analyzed using bioinformatics. 293 cells were transfected with wildtype (WT) or mutanttype (MT) GPD1L and SCN5A plasmids. Successful transfection of GPD1L in 293 cells was verified by western blotting. Wholecell patchclamp recording, confocal microscopic observation and western blotting were used to uncover the potential mechanism of GPD1L P112L in ERS. The results of western blotting indicated that the expression of the GPD1L protein was lower in the MT group compared with that in the WT group, but the mock group did not express the GPD1L protein. The wholecell patchclamp recording results indicated that the activation current density of INa (at 30 mV) was ~60% lower in the MT group compared with the WT group (P<0.01). The mutation caused the inactivation voltage to move in a negative direction by ~3 mV compared with that of the WT group. However, there were no significant betweengroup differences in the steady activation, steady inactivation, and steady recovery of INa. Confocal microscopy demonstrated that MT GPD1L was less expressed near the cell membrane and more expressed in the cytoplasm compared with WT GPD1L. Both WT and MT GPD1L were highly expressed in the cytoplasm and in small amounts in the nucleus. In conclusion, the GPD1L P112L mutation decreased INa activation and GPD1L cell expression, including in the region near the cell membrane. These results suggest that GPD1L P112L may be a pathogenic genetic mutation associated with ERS.
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Base de dados:
MEDLINE
Assunto principal:
Morte Súbita Cardíaca
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Miócitos Cardíacos
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Canal de Sódio Disparado por Voltagem NAV1.5
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Glicerolfosfato Desidrogenase
Tipo de estudo:
Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article