Long QT Syndrome Type 3 (LQT 3)Long QT Syndrome Type 3 (LQT 3)Mutations in SCN5A (Na+ Channel, IMutations in SCN5A (Na+ Channel, INaNa))

BME 301BME 301

Silvia Castillo, Qaiyim Cheeseborough, Silvia Castillo, Qaiyim Cheeseborough, Victoria Reyes, Kin SiuVictoria Reyes, Kin Siu

Introduction to LQTIntroduction to LQT

Disorder caused by Disorder caused by mutations in cardiac mutations in cardiac ion channelsion channelsMost associated with Most associated with K+ channelsK+ channels

SymptomsSymptoms

Fainting (syncope)Fainting (syncope)

SeizuresSeizures

Cardiac arrestCardiac arrest

Sudden DeathSudden Death

DiagnosisDiagnosis

Diagnosis is Diagnosis is preformed by preformed by analyzing the EKG analyzing the EKG readings in response readings in response to the T – wave.to the T – wave.

A autopsy may be A autopsy may be conducted of LQT 3 conducted of LQT 3 syndrome through syndrome through examining the SCN5A examining the SCN5A genegene

Normal EKG

Long QT syndrome

Genetic Picture of SCN5AGenetic Picture of SCN5A

Located on human 3p21 Located on human 3p21 chromosomechromosome

Encodes alpha subunit Encodes alpha subunit of cardiac sodium of cardiac sodium channel proteinchannel protein

Specific MutationsSpecific Mutations

17 known mutations, 14 are single 17 known mutations, 14 are single nucleotidenucleotide

Codon LocationCodon Location NucleotideNucleotide Amino acidAmino acid

16231623 CGA->CAACGA->CAA Arg->GlnArg->Gln

16441644 CGC->CACCGC->CAC Arg->HisArg->His

17771777 GTG->ATGGTG->ATG Val->MetVal->Met

Physical CharacteristicsPhysical Characteristics

2016 amino acids2016 amino acidsSequence – 4 internal Sequence – 4 internal repeats, with 5 hydrophobic repeats, with 5 hydrophobic segments and 1 positively segments and 1 positively charged segment eachcharged segment each

FunctionFunction

Forms voltage-Forms voltage-dependent, sodium dependent, sodium selective channelselective channelPositively charged Positively charged segments most likely segments most likely the voltage sensorsthe voltage sensorsResponsible for initial Responsible for initial upstroke in an action upstroke in an action potentialpotential

Protein Mechanism for DisorderProtein Mechanism for Disorder

Poorly understoodPoorly understood

III-IV linker region as blocking particleIII-IV linker region as blocking particle

C-Terminus as a docking stationC-Terminus as a docking station

Mutations at these regions can cause failure Mutations at these regions can cause failure in inactivationin inactivation

Fraction of Na+ channels fail to inactivateFraction of Na+ channels fail to inactivate

Cause sustained Na+ ion influx Cause sustained Na+ ion influx

Leads to longer QT-intervals in an Leads to longer QT-intervals in an electrocardiogramelectrocardiogram

Mechanism for DisorderMechanism for Disorder

Drug Treatment - 1Drug Treatment - 1

LidocaineLidocaine Most commonly usedMost commonly used Inhibits the influx of sodiumInhibits the influx of sodium

MexiletineMexiletine Orally administeredOrally administered Mechanism similar to Mechanism similar to

LidocaineLidocaine

Drug Treatment - 2Drug Treatment - 2

Drug Treatment - 3Drug Treatment - 3

FlecainideFlecainide Mechanism similar Mechanism similar

to Lidocaineto Lidocaine

Risk FactorsRisk Factors

History of syncopeHistory of syncopeDuration of episode and QT intervalDuration of episode and QT intervalCongenital deafnessCongenital deafnessMale childrenMale childrenFemale pregnancy cardiac events are Female pregnancy cardiac events are commoncommon

StatisticsStatistics

8% of all LQT carriers have SCN5A 8% of all LQT carriers have SCN5A mutationsmutationsCase study – found LQT-3 more lethalCase study – found LQT-3 more lethalOnset: 50% by 12 years; 90% by 40 yearsOnset: 50% by 12 years; 90% by 40 years

ReferencesReferencesNeuromuscular Disease Center. Neuromuscular Disease Center. ION CHANNELS, TRANSMITTERS, ION CHANNELS, TRANSMITTERS, RECEPTORS & DISEASERECEPTORS & DISEASE. 10 Feb 2000. . 10 Feb 2000.

< < http://www.neuro.wustl.edu/neuromuscular/mother/chan.htmlhttp://www.neuro.wustl.edu/neuromuscular/mother/chan.html>>

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