Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants

Tan, Bi Hua; Valdivia, Carmen R.; Rok, Benjamin A.; Ye, Bin; Ruwaldt, Karen M.; Tester, David J.; Ackerman, Michael J.; Makielski, Jonathan C.

doi:10.1016/j.hrthm.2005.04.021

Cited by 111 publications

(105 citation statements)

References 16 publications

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“…Humans simultaneously express two WT splice variants at position 1077, a glutamine (Q1077) and a deletion (Q1077del). 53 The Q1077 decreases sodium current density when co-expressed with certain polymorphisms whereas the Q1077del does not significantly alter sodium current density. 53 Our mutation was expressed using a clone encoding for the Q1077del splice variant.…”

Section: Discussionmentioning

confidence: 98%

A sodium channel pore mutation causing Brugada syndrome

et al. 2007

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BACKGROUND-Brugada and Long QT type 3 syndromes are linked to sodium channel mutations and clinically cause arrhythmias that lead to sudden death. We have identified a novel threonine to isoleucine missense mutation at position 353 (T353I) adjacent to the pore-lining region of domain I of the cardiac sodium channel (SCN5a) in family with Brugada syndrome. Both male and female carriers are symptomatic at young ages, have typical Brugada-type ECG changes, and have relatively normal corrected QT intervals.

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Section: Discussionmentioning

confidence: 98%

A sodium channel pore mutation causing Brugada syndrome

et al. 2007

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“…20,[23][24][25] Since patient B22 carries both a heterozygous S1553R and a homozygous H558R, there is a possibility that H558R may ameliorate the clinical severity of this patient. P1090L (identified in patients B10, B15, and B25) and R1193Q (identified in patients B02 and B24) are Asian-specific polymorphisms, 20,26,27) although R1193Q has also been reported as a BrS and LQTScausing mutation. 28,29) R1232W (identified in patient B15) was originally reported as a rare polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Identification of Six Novel SCN5A Mutations in Japanese Patients With Brugada Syndrome

et al. 2011

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SummaryMutations in SCN5A are linked to Brugada syndrome in approximately 20% of all cases (BrS1). Several dozen distinct SCN5A mutations in BrS1 have been associated with the increased risk of cardiac arrhythmias. However, the genotype-phenotype relationship remains elusive. The current study analyzed the SCN5A gene to elucidate the potential variability of clinical features in Japanese BrS1 subjects. Subjects of the present study included 30 probands (25 male subjects, 45 ± 15 years of age) with Brugada-pattern ECG. Seven patients had been resuscitated from cardiopulmonary arrest (CPA group). Another 10 patients had a history of syncope (Sy group), and 13 more remain asymptomatic (Asy group). We identified 8 different SCN5A mutations, including 6 novel mutations (CPA group: 1/7, Sy group: 3/10, Asy group: 4/13). An A735E mutation (located at segment (S)1 in domain (D)2) was identified in the CPA group. A novel splice acceptor site mutation (c.393-1c>t), which may produce a prematurely truncated protein, was identified in the Sy group. An E1784K mutation (C-terminus) and a novel mutation V1951M (C-terminus) were also identified in the Sy group. Four novel missense mutations, A586T (D1-D2 linker), R689H (D1-D2 linker), S1553R (S1-S2 in D4), and Q1706H (S5-Pore in D4) were identified in the Asy group. These data may help us understand the genetic heterogeneity of BrS1, which is more prevalent in Japanese than in whites and other ethnic groups. (Int Heart J 2011; 52: 27-31) Key words: Brugada syndrome, SCN5A, Mutation T he Brugada syndrome (BrS), characterized by ST-segment elevations in the right precordial ECG leads without structural heart disease, is a hereditable disease associated with an increased risk of sudden death due to polymorphic ventricular tachycardia or ventricular fibrillation (VF).1) Genetic analyses of BrS revealed that BrS is genetically heterogeneous, and is linked to at least 7 different genes. [2][3][4][5][6][7][8] Mutations in SCN5A, which encodes the pore-forming subunit of the cardiac voltage-gated sodium channel, have been associated with the major form of BrS (BrS1) in approximately 20% of cases. [9][10][11] The clinical severity of BrS may vary with the responsible genes and/or mutation sites, although the genotypephenotype relationship remains poorly characterized. The presence of SCN5A mutations is not related to the severity of the disease.9,10,12) However, Meregalli, et al have recently reported that the type of SCN5A mutation in BrS1 in European countries may determine the clinical severity.13) Because the clinical features of BrS vary among different ethnicities, 14,15) it is of great value to investigate the genotype-phenotype relationship of BrS in Asians in whom the ratio of BrS patients is relatively high compared to subjects from different ethnic backgrounds.In the present study, we analyzed the SCN5A gene to elucidate the potential variability of clinical features of BrS1 subjects recruited from Gunma University Hospital. Consequently, we identified 8 SCN5A mutations, incl...

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“…AC1377587)] in the pcDNA3 plasmid vector (Invitrogen, Carlsbad, CA) as previously reported [11,12]. All clones were sequenced to confirm integrity and to ensure the presence of the target mutations without other substitutions.…”

Section: Methodsmentioning

confidence: 99%

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

Tester

et al. 2018

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Introduction: Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. Methods and Results: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (INa) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak INa and a significantly increased late INa compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak INa of the mutant channel and inhibited the increased late INa of the mutant channel. Conclusion: SCN5A-N406K channel displays both “gain-of-function” in late INa and “loss-of-function” in peak INa density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both “gain-of-function” and “loss-of-function” of the mutant sodium channel.

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Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants

Cited by 111 publications

References 16 publications

A sodium channel pore mutation causing Brugada syndrome

A sodium channel pore mutation causing Brugada syndrome

Identification of Six Novel SCN5A Mutations in Japanese Patients With Brugada Syndrome

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients

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