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 J. (2009). Unique mixed phenotype and unexpected functional effect revealed by novel compound heterozygosity mutations involving SCN5A. Heart rhythm, 6(8), pp. 1170-1175. Elsevier 10.1016/j.hrthm.2009.04.034

Full text not available from this repository. (Request a copy)


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.


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.


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.


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.


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 Na(V)1.5 channels in vitro.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Medeiros Domingo, Argelia


600 Technology > 610 Medicine & health








Argelia Medeiros Domingo

Date Deposited:

19 Jun 2014 11:19

Last Modified:

05 Dec 2022 14:28

Publisher DOI:


PubMed ID:




Actions (login required)

Edit item Edit item
Provide Feedback