The common SCN5A mutation R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium channel

Wang, Qing Kenneth; Chen, S.; Chen, Qiuyun; Wan, Xiaoping; Shen, Jinglai; Hoeltge, Gerald A.; Timur, Ayse Anil; Keating, Mark T.; Kirsch, Glenn E.

doi:10.1136/jmg.2003.013300

Cited by 79 publications

(78 citation statements)

References 53 publications

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“…3B) in both groups. In agreement with our suggestion that amino acid mutations that occur in these regions will be selected against because they might cause pathology, we indicate in the figure mutations that have been noted in the human clinical literature and associated with muscular, cardiac or neurological disease (Wei et al, 1999; Bendahhou et al, 2002;Splawski et al, 2002;Tan et al, 2003;Tian et al, 2004;Wang et al, 2004; Berkovic et al, 2004). These mutations flank (Fig.…”

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confidence: 62%

“…We do not know what molecular events account for altered expression of Nav1.4a in electric fish, but analysis of regulatory regions in these genes compared with the regulatory regions in related non-electric fish will probably shed light on this. Na + channel genes are normally under strong negative selection as evidenced by the large catalog of channelopathies (diseases attributed to mutations in ion channels) (Wei et al, 1999; Bendahhou et al, 2002;Splawski et al, 2002;Tan et al, 2003;Tian et al, 2004;Wang et al, 2004; Berkovic et al, 2004). We reasoned that in both lineages of electric fish Nav1.4a would be freed from many selective constraints associated with muscle expression as electrocytes are not contractile and mutations in Nav1.4a would have no effect on a fish's motility.…”

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confidence: 99%

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Molecular evolution of communication signals in electric fish

Zakon

Zwickl

et al. 2008

Journal of Experimental Biology

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SummaryAnimal communication systems are subject to natural selection so the imprint of selection must reside in the genome of each species. Electric fish generate electric organ discharges (EODs) from a muscle-derived electric organ (EO) and use these fields for electrolocation and communication. Weakly electric teleosts have evolved at least twice (mormyriforms, gymnotiforms) allowing a comparison of the workings of evolution in two independently evolved sensory/motor systems. We focused on the genes for two Na + channels, Nav1.4a and Nav1.4b, which are orthologs of the mammalian muscle-expressed Na + channel gene Nav1.4. Both genes are expressed in muscle in non-electric fish. Nav1.4b is expressed in muscle in electric fish, but Nav1.4a expression has been lost from muscle and gained in the evolutionarily novel EO in both groups. We hypothesized that Nav1.4a might be evolving to optimize the EOD for different sensory environments and the generation of species-specific communication signals. We obtained the sequence for Nav1.4a from non-electric, mormyriform and gymnotiform species, estimated a phylogenetic tree, and determined rates of evolution. We observed elevated rates of evolution in this gene in both groups coincident with the loss of Nav1.4a from muscle and its compartmentalization in EO. We found amino acid substitutions at sites known to be critical for channel inactivation; analyses suggest that these changes are likely to be the result of positive selection. We suggest that the diversity of EOD waveforms in both groups of electric fish is correlated with accelerations in the rate of evolution of the Nav1.4a Na + channel gene due to changes in selection pressure on the gene once it was solely expressed in the EO.Key words: sodium channels, molecular evolution, communication, electric fish, electric organ, fish. THE JOURNAL OF EXPERIMENTAL BIOLOGY Evolution of electric fish signalsAfrica. This allows us to compare the workings of evolution in two independently evolved sensory/motor systems (Bullock et al., 2005). Their sensory receptors, EOs, and central sensory processing and motor control areas are remarkably similar in a striking case of parallel evolution. Electric fish are, therefore, good model organisms for investigating whether parallel evolution has also occurred on the molecular level.Electric fish lend themselves to a molecular evolutionary analysis in that electric signals are already in the currency of the nervous system: electricity. Because of this, electric signals are easily understood and analyzed in terms of the biophysics of ion currents and associated with a manageable number of candidate genes (mainly encoding Na + and K + channels) whose expression can be localized to sensory and motor structures.Electric fish are excellent animals for studying the coordinated evolution of sensory and motor processes. Electric fish generate EO discharges (EODs) from a muscle-derived EO and sense these fields with special sensory receptors called electroreceptors, presumably derived from the same...

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confidence: 62%

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confidence: 99%

Molecular evolution of communication signals in electric fish

Zakon

Zwickl

et al. 2008

Journal of Experimental Biology

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“…CONCLUSION : Le polymorphisme R1193Q est, sans contredit, associé à des anomalies de la conduction électrique dans le coeur. the R1193Q mutation was reported to cause either LQTS (11,12) or BS (13,14) or to be associated with cardiac conductance abnormalities in a four-generation Chinese family (15). However, no direct links have been associated with the presence of the mutation and electrical abnormalities or sudden deaths in this family.…”

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confidence: 81%

“…The R1193Q mutation has recently been identified in patients with acquired LQTS, BS and cardiac conductance disease (11)(12)(13)15).…”

Section: Discussionmentioning

confidence: 99%

Nav1.5/R1193Q polymorphism is associated with both long QT and Brugada syndromes

Huang

Zhao

Barrane

et al. 2006

Canadian Journal of Cardiology

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“…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.…”

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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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The common SCN5A mutation R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium channel

Cited by 79 publications

References 53 publications

Molecular evolution of communication signals in electric fish

Molecular evolution of communication signals in electric fish

Nav1.5/R1193Q polymorphism is associated with both long QT and Brugada syndromes

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

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