title: Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.
abstract: OBJECTIVE
  Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1's 3' untranslated region (3'UTR).
  
  
  RESULTS
  This study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1's 3'UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1's 3'UTR with the derived SNP variants was lower than the expression of the 3'UTR with the ancestral SNP variants.
  
  
  CONCLUSIONS
  Our data indicate that 3'UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele.
authors.affiliation: Heart Failure Research Center, Academic Medical Center,  University of Amsterdam, Amsterdam,  the Netherlands.
authors.forename: Ahmad S
authors.initials: AS
authors.lastname: Amin
authors.forename: John R
authors.initials: JR
authors.lastname: Giudicessi
authors.forename: Anke J
authors.initials: AJ
authors.lastname: Tijsen
authors.forename: Anne M
authors.initials: AM
authors.lastname: Spanjaart
authors.forename: Yolan J
authors.initials: YJ
authors.lastname: Reckman
authors.forename: Christine A
authors.initials: CA
authors.lastname: Klemens
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tanck
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Kapplinger
authors.forename: Nynke
authors.initials: N
authors.lastname: Hofman
authors.forename: Moritz F
authors.initials: MF
authors.lastname: Sinner
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Wino J
authors.initials: WJ
authors.lastname: Wijnen
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000483:Alleles; D000818:Animals; D004562:Electrocardiography; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000201:enzymology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051381:Rats; D029597:Romano-Ward Syndrome / Q000201:enzymology / Q000235:genetics*; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D008156:Luciferases