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

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 Na(V)1.5 channels in vitro.

• Authors: Argelia Medeiros-Domingo, Bi-Hua Tan, Pedro Iturralde-Torres, David J Tester, Teresa Tusié-Luna, Jonathan C Makielski, Michael J Ackerman
• Journal: Heart rhythm (Heart Rhythm) Vol. 6 Issue 8 Pg. 1170-5 (Aug 2009) ISSN: 1556-3871 [Electronic] United States
• PMID: 19632629 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Muscle Proteins
• NAV1.5 Voltage-Gated Sodium Channel
• SCN5A protein, human
• Sodium Channels

Topics

• Analysis of Variance
• Brugada Syndrome (genetics)
• Fatal Outcome
• Fever (complications)
• Heterozygote
• Humans
• Infant
• Long QT Syndrome (genetics)
• Male
• Muscle Proteins (genetics)
• NAV1.5 Voltage-Gated Sodium Channel
• Pedigree
• Phenotype
• Risk Factors
• Sodium Channels (genetics)
• Tachycardia, Ventricular (etiology, genetics)