Abstract 13643: MicroRNA-Mediated Reduction of Mutant Kv7.1 Expression by Functional Variants in the 3’Untranslated Region of KCNQ1 Contributes to the Auditory Phenotype and Parental Non-Penetrance Associated with Jervell and Lange-Nielsen Syndrome Compound Heterozygosity
Introduction: Jervell and Lange-Nielsen syndrome (JLNS) is a rare autosomal recessive form of long QT syndrome (LQTS) that most commonly stems from either homozygous or compound heterozygous mutations involving both KCNQ1 alleles and is characterized by deafness, markedly prolonged QT interval, and high risk of sudden death. At present, it is not understood why some KCNQ1 compound heterozygotes present without an auditory phenotype and why many JLNS parents exhibit no or only minimal evidence of a QT abnormality. Here, we hypothesize, that the minor alleles of SNPs rs2519184 (A) and rs8234 (G) in the 3’untranslated region (3’UTR) of KCNQ1, that function as allele-specific modifiers of LQT1 disease severity via the microRNA-mediated reduction of Kv7.1 expression, may conceal the cardiac phenotype in parents of JLNS children by reducing the ratio of mutant to wild-type Kv7.1 subunits, while exacerbating the cardiac and auditory phenotypes in KCNQ1 compound heterozygotes by further reducing residual Kv7.1 function resulting in JLNS.
Methods: In this IRB-approved study, the families of 6 KCNQ1 compound heterozygotes (2 JLNS and 4 compound LQT1 with intact hearing) were analyzed for the presence of SNPs within the 3’UTR of KCNQ1 using DNA sequencing. Cis/trans phase determination of the 3’UTR haplotype was accomplished by pedigree analysis.
Results: Overall, 3/4 (75%) parents of a JLNS child, but only 1/8 (12.5%) parents of a compound LQT1 child harbored the minor AG 3’UTR suppressive haplotype on their mutant allele (p < 0.05). Interestingly, compound LQT1 parents featured a higher average QTc (452 ± 31) than JLNS parents (409 ± 17, p < 0.05). Furthermore, those KCNQ1 compound heterozygotes that inherited missense or splice-site mutations with the minor AG 3’UTR haplotype in cis presented with JLNS, whereas those KCNQ1 compound heterozygotes that inherited missense or splice-site mutations with the major GA 3’UTR haplotype in cis presented with LQT1.
Conclusions: This study provides initial evidence that the suppression of the mutant KCNQ1 allele by the minor alleles of SNPs in the 3’UTR of KCNQ1 may play a role in determining the auditory phenotype of KCNQ1 compound heterozygotes and partly explain the high rate of non-penetrance associated with JLNS parents.
- © 2011 by American Heart Association, Inc.