+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome



Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome



Circulation 114(19): 2026-2033



Loss-of-function mutations in SCN5A have been associated with the Brugada syndrome. We report the first Brugada syndrome family with compound heterozygous mutations in SCN5A. The proband inherited 1 mutation from each parent and transmitted 1 to each daughter. The effects of the mutations on the function of the sodium channel were evaluated with heterologous expression in TSA201 cells, patch-clamp study, and confocal microscopy. Genetic analysis revealed that the proband carried 2 heterozygous missense mutations (P336L and I1660V) on separate alleles. He displayed a coved-type ST-segment elevation and a prolonged PR interval (280 ms). One daughter inherited P336L and exhibited a prolonged PR (210 ms). The other daughter inherited mutation I1660V and displayed a normal PR interval. Both daughters had a slightly elevated, upsloping ST-segment elevation. The parents had normal ECGs. Patch-clamp analysis showed that the P336L mutation reduced I(Na) by 85% relative to wild type. The I1660V mutation produced little measurable current, which was rescued by room temperature incubation for 48 hours. Sodium channel blockers also rescued the I1660V current, with mexiletine proving to be the most effective. Confocal immunofluorescence showed that I1660V channels conjugated to green fluorescent protein remained trapped in intracellular organelles. Mutation P336L produced a reduction in cardiac I(Na), whereas I1660V abolished it. Only the proband carrying both mutations displayed the Brugada syndrome phenotype, whereas neither mutation alone produced the clinical phenotype. I1660V channels could be rescued pharmacologically and by incubation at room temperature. The present data highlight the role of compound heterozygosity in modulating the phenotypic expression and penetrance of Brugada syndrome.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 012956211

Download citation: RISBibTeXText

PMID: 17075016

DOI: 10.1161/circulationaha.106.627489


Related references

Human Scn5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovascular Research 44(3): 507-517, 1999

Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovascular Research 44(3): 507-517, 2000

Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. Journal of Biological Chemistry 276(33): 30623-30630, 2001

Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations. Journal of Biomedical Science 16: 23, 2009

Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. Journal of Clinical Investigation 118(6): 2260-2268, 2008

Compound heterozygous mutations in the SCN5A-encoded Nav1.5 cardiac sodium channel resulting in atrial standstill and His-Purkinje system disease. Journal of Pediatrics 165(5): 1050-1052, 2015

Mutations in an alternately processed sodium channel beta-1 subunit associated with Brugada syndrome and cardiac conduction defect. 2007

Differential effects of cardiac sodium channel mutations on initiation of ventricular arrhythmias in patients with Brugada syndrome. Heart Rhythm 6(4): 487-492, 2009

A heterozygous deletion mutation in the cardiac sodium channel gene SCN5A with loss- and gain-of-function characteristics manifests as isolated conduction disease, without signs of Brugada or long QT syndrome. Plos One 8(6): E67963, 2014

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 7(1): 33-46, 2011

A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. Journal of Molecular and Cellular Cardiology 38(6): 969-981, 2005

Characterization of two mutations in SCN5A sodium channel causing Brugada syndrome. Circulation 100(18 SUPPL ): I 278, Nov 2, 1999

Novel sodium channel SCN5A mutations in Brugada syndrome patients from Greece. International Journal of Cardiology 145(1): 45-48, 2011

Characterization of a novel cardiac sodium channel mutation in the Brugada syndrome. Biophysical Journal 84(2 Part 2): 217a, 2003

Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations. Circulation. Cardiovascular Genetics 7(2): 123-131, 2015