Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A

Argelia Medeiros-Domingo, Bi Hua Tan, Pedro Iturralde-Torres, David J. Tester, Teresa Tusié-Luna, Jonathan C. Makielski, Michael John Ackerman

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Functional characterization of mutations involving the SCN5A-encoded cardiac sodium channel has established the pathogenic mechanisms for type 3 long QT syndrome and type 1 Brugada syndrome and has provided key insights into the physiological importance of essential structure-function domains. Objective: This study sought to present the clinical and biophysical phenotypes discerned from compound heterozygosity mutations in SCN5A on different alleles in a toddler diagnosed with QT prolongation and fever-induced ventricular arrhythmias. Methods: A 22-month-old boy presented emergently with fever and refractory ventricular tachycardia. Despite restoration of sinus rhythm, the infant sustained profound neurological injury and died. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open-reading frame/splice mutational analysis of the 12 known long QT syndrome susceptibility genes was performed. Results: The infant had 2 SCN5A mutations: a maternally inherited N-terminal frame shift/deletion (R34fs/60) and a paternally inherited missense mutation, R1195H. The mutations were engineered by site-directed mutagenesis and heterologously expressed transiently in HEK293 cells. As expected, the frame-shifted and prematurely truncated peptide, SCN5A-R34fs/60, showed no current. SCN5A-R1195H had normal peak and late current but abnormal voltage-dependent gating parameters. Surprisingly, co-expression of SCN5A-R34fs/60 with SCN5A-R1195H elicited a significant increase in late sodium current, whereas co-expression of SCN5A-WT with SCN5A-R34fs/60 did not. Conclusions: A severe clinical phenotype characterized by fever-induced monomorphic ventricular tachycardia and QT interval prolongation emerged in a toddler with compound heterozygosity involving SCN5A: R34fs/60, and R1195H. Unexpectedly, the 94-amino-acid fusion peptide derived from the R34fs/60 mutation accentuated the late sodium current of R1195H-containing NaV1.5 channels in vitro.

Original languageEnglish (US)
Pages (from-to)1170-1175
Number of pages6
JournalHeart Rhythm
Volume6
Issue number8
DOIs
StatePublished - Aug 2009

Fingerprint

Phenotype
Mutation
Fever
Ventricular Tachycardia
Romano-Ward Syndrome
Sodium
Brugada Syndrome
Long QT Syndrome
Peptides
Sodium Channels
HEK293 Cells
Missense Mutation
Site-Directed Mutagenesis
DNA Sequence Analysis
Open Reading Frames
Cardiac Arrhythmias
Alleles
High Pressure Liquid Chromatography
Amino Acids
Polymerase Chain Reaction

Keywords

  • Channelopathies
  • Long QT syndrome
  • Sodium channel
  • Sudden death
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Medeiros-Domingo, A., Tan, B. H., Iturralde-Torres, P., Tester, D. J., Tusié-Luna, T., Makielski, J. C., & Ackerman, M. J. (2009). Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A. Heart Rhythm, 6(8), 1170-1175. https://doi.org/10.1016/j.hrthm.2009.04.034

Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A. / Medeiros-Domingo, Argelia; Tan, Bi Hua; Iturralde-Torres, Pedro; Tester, David J.; Tusié-Luna, Teresa; Makielski, Jonathan C.; Ackerman, Michael John.

In: Heart Rhythm, Vol. 6, No. 8, 08.2009, p. 1170-1175.

Research output: Contribution to journalArticle

Medeiros-Domingo, A, Tan, BH, Iturralde-Torres, P, Tester, DJ, Tusié-Luna, T, Makielski, JC & Ackerman, MJ 2009, 'Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A', Heart Rhythm, vol. 6, no. 8, pp. 1170-1175. https://doi.org/10.1016/j.hrthm.2009.04.034
Medeiros-Domingo A, Tan BH, Iturralde-Torres P, Tester DJ, Tusié-Luna T, Makielski JC et al. Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A. Heart Rhythm. 2009 Aug;6(8):1170-1175. https://doi.org/10.1016/j.hrthm.2009.04.034
Medeiros-Domingo, Argelia ; Tan, Bi Hua ; Iturralde-Torres, Pedro ; Tester, David J. ; Tusié-Luna, Teresa ; Makielski, Jonathan C. ; Ackerman, Michael John. / Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A. In: Heart Rhythm. 2009 ; Vol. 6, No. 8. pp. 1170-1175.
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AU - Tan, Bi Hua

AU - Iturralde-Torres, Pedro

AU - Tester, David J.

AU - Tusié-Luna, Teresa

AU - Makielski, Jonathan C.

AU - Ackerman, Michael John

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N2 - Background: Functional characterization of mutations involving the SCN5A-encoded cardiac sodium channel has established the pathogenic mechanisms for type 3 long QT syndrome and type 1 Brugada syndrome and has provided key insights into the physiological importance of essential structure-function domains. Objective: This study sought to present the clinical and biophysical phenotypes discerned from compound heterozygosity mutations in SCN5A on different alleles in a toddler diagnosed with QT prolongation and fever-induced ventricular arrhythmias. Methods: A 22-month-old boy presented emergently with fever and refractory ventricular tachycardia. Despite restoration of sinus rhythm, the infant sustained profound neurological injury and died. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open-reading frame/splice mutational analysis of the 12 known long QT syndrome susceptibility genes was performed. Results: The infant had 2 SCN5A mutations: a maternally inherited N-terminal frame shift/deletion (R34fs/60) and a paternally inherited missense mutation, R1195H. The mutations were engineered by site-directed mutagenesis and heterologously expressed transiently in HEK293 cells. As expected, the frame-shifted and prematurely truncated peptide, SCN5A-R34fs/60, showed no current. SCN5A-R1195H had normal peak and late current but abnormal voltage-dependent gating parameters. Surprisingly, co-expression of SCN5A-R34fs/60 with SCN5A-R1195H elicited a significant increase in late sodium current, whereas co-expression of SCN5A-WT with SCN5A-R34fs/60 did not. Conclusions: A severe clinical phenotype characterized by fever-induced monomorphic ventricular tachycardia and QT interval prolongation emerged in a toddler with compound heterozygosity involving SCN5A: R34fs/60, and R1195H. Unexpectedly, the 94-amino-acid fusion peptide derived from the R34fs/60 mutation accentuated the late sodium current of R1195H-containing NaV1.5 channels in vitro.

AB - Background: Functional characterization of mutations involving the SCN5A-encoded cardiac sodium channel has established the pathogenic mechanisms for type 3 long QT syndrome and type 1 Brugada syndrome and has provided key insights into the physiological importance of essential structure-function domains. Objective: This study sought to present the clinical and biophysical phenotypes discerned from compound heterozygosity mutations in SCN5A on different alleles in a toddler diagnosed with QT prolongation and fever-induced ventricular arrhythmias. Methods: A 22-month-old boy presented emergently with fever and refractory ventricular tachycardia. Despite restoration of sinus rhythm, the infant sustained profound neurological injury and died. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open-reading frame/splice mutational analysis of the 12 known long QT syndrome susceptibility genes was performed. Results: The infant had 2 SCN5A mutations: a maternally inherited N-terminal frame shift/deletion (R34fs/60) and a paternally inherited missense mutation, R1195H. The mutations were engineered by site-directed mutagenesis and heterologously expressed transiently in HEK293 cells. As expected, the frame-shifted and prematurely truncated peptide, SCN5A-R34fs/60, showed no current. SCN5A-R1195H had normal peak and late current but abnormal voltage-dependent gating parameters. Surprisingly, co-expression of SCN5A-R34fs/60 with SCN5A-R1195H elicited a significant increase in late sodium current, whereas co-expression of SCN5A-WT with SCN5A-R34fs/60 did not. Conclusions: A severe clinical phenotype characterized by fever-induced monomorphic ventricular tachycardia and QT interval prolongation emerged in a toddler with compound heterozygosity involving SCN5A: R34fs/60, and R1195H. Unexpectedly, the 94-amino-acid fusion peptide derived from the R34fs/60 mutation accentuated the late sodium current of R1195H-containing NaV1.5 channels in vitro.

KW - Channelopathies

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