TY - JOUR
T1 - Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A
AU - Medeiros-Domingo, Argelia
AU - Tan, Bi Hua
AU - Iturralde-Torres, Pedro
AU - Tester, David J.
AU - Tusié-Luna, Teresa
AU - Makielski, Jonathan C.
AU - Ackerman, Michael J.
N1 - Funding Information:
Drs. Medeiros-Domingo and Tan contributed equally to this work. Dr. Medeiros received financial support through a CONACyT and FUNSALUD fellowship. Dr. Tan was supported by the American Heart Association, a Greater Midwest Affiliate Postdoctoral fellowship, and National Institutes of Health grant HL71092 to Dr. Makielski. Dr. Ackerman's research program is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program, the Dr. Scholl Foundation, the C.J. Foundation for SIDS, the American Heart Association, and the National Institutes of Health (HD42569). Dr Ackerman as a consultant for PGxHealth. Intellectual properly derived from MJA's research program resulted in license agreements in 2004 between Mayo Clinic Health Solutions (formerly Mayo Medical Ventures) and PGxHealth (formerly Genaissance Pharmaceuticals).
PY - 2009/8
Y1 - 2009/8
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.
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U2 - 10.1016/j.hrthm.2009.04.034
DO - 10.1016/j.hrthm.2009.04.034
M3 - Article
C2 - 19632629
AN - SCOPUS:67650741355
SN - 1547-5271
VL - 6
SP - 1170
EP - 1175
JO - Heart Rhythm
JF - Heart Rhythm
IS - 8
ER -