What question did this study set out to answer?

Investigate the functional and clinical consequences of novel compound heterozygous SCN5A mutations (P336L and I1660V) identified in a patient with Brugada syndrome.

October 31, 2006CirculationOpen Access

Compound Heterozygous Mutations P336L and I1660V in the Human Cardiac Sodium Channel Associated With the Brugada Syndrome

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Population

A Brugada syndrome family (proband, 2 daughters, parents) and TSA201 cells expressing mutant SCN5A channels.

Comparison

SCN5A mutations P336L and I1660V… vs Wild type SCN5A channels and clinical phenotype…

Design

Preclinical

Authors

JCJonathan M. CordeiroUniversidad Complutense de Madrid HBHéctor Barajas-MartínezElectrophysiology KHKui HongElectrophysiology

Discussion

Member takes

Implication

Compound SCN5A heterozygosity may modulate Brugada penetrance; leaves open validation in human cohorts.

Key Points

Investigate the functional and clinical consequences of novel compound heterozygous SCN5A mutations (P336L and I1660V) identified in a patient with Brugada syndrome.
Conducted familial genetic screening and electrocardiographic (ECG) assessments across three generations.
Expressed wild-type and mutant sodium channels heterologously in TSA201 cells to evaluate electrophysiological properties via patch-clamp recordings.
Analyzed channel trafficking with confocal immunofluorescence microscopy and tested rescue of trafficking-deficient channels using room temperature incubation and sodium channel blockers.
The compound heterozygous proband showed coved-type ST-segment elevation and prolonged PR interval (280 ms), whereas single-mutation carriers exhibited mild (daughter with P336L: PR 210 ms) or absent clinical phenotypes.
Electrophysiological analysis demonstrated that the P336L mutation reduced peak inward sodium current (I_Na) by 85% compared to wild type, while the I1660V mutation yielded virtually no measurable current due to intracellular retention.
The trafficking-deficient I1660V channels were functionally rescued by 48-hour room-temperature incubation and by pharmacological treatment with sodium channel blockers, with mexiletine demonstrating the greatest efficacy.

Structured PICO

Population

A Brugada syndrome family (proband, 2 daughters, parents) and TSA201 cells expressing mutant SCN5A channels.

Intervention

SCN5A mutations P336L and I1660V; pharmacological rescue with sodium channel blockers (mexiletine) and room temperature incubation.

Comparator

Wild type SCN5A channels and clinical phenotype of single mutation carriers.

Outcome

Sodium channel function (I(Na) current) and clinical phenotype (ECG findings).surrogate

Compound heterozygosity of SCN5A mutations (P336L and I1660V) modulates the phenotypic expression and penetrance of Brugada syndrome, with neither mutation alone producing the full clinical phenotype.

Cite This Study

Cordeiro et al. (2006) studied this question.

synapsesocial.com/papers/6a7ae222e357fbdac589b2f0 https://doi.org/10.1161/circulationaha.106.627489

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Compound Heterozygous Mutations P336L and I1660V in the Human Cardiac Sodium Channel Associated With the Brugada Syndrome

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Compound Heterozygous Mutations P336L and I1660V in the Human Cardiac Sodium Channel Associated With the Brugada Syndrome

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Also Consider

Also Consider