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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


Inherited cardiac diseases are often caused by a single autosomal-dominant mutation in a gene encoding for a cardiac ion channel or a sarcomere protein. These single mutations can cause life-threatening arrhythmias and sudden death in heterozygous mutation carriers. This recognition has been the basis for world-wide staggering numbers of subjects and families counselled for inherited cardiac diseases and treated based on finding disease-causing mutations. However, treating patients is greatly hampered by the growing awareness that simple carriership of a mutation often fails to predict clinical outcome: many carriers never develop clinically relevant disease while others are severely affected at a young age. It is still largely elusive what determines this large variability in disease severity, where even family members that carry an identical mutation still have large differences in disease severity. Consequently, it remains difficult to identify individuals at the highest risk, which hampers critical decisions on most appropriate therapy.

Pericardial Disease


We hypothesized that single nucleotide polymorphisms (SNPs) in the 3’untranslated region (3’UTR) can drive the increased or decreased translation of one allele over the other. This is of clinical relevance when one of the two alleles harbors a disease-causing mutation. Changing the relative expression of the normal allele versus the mutation-containing allele alters the balance between normal and mutant proteins. SNPs in the 3'UTR may alter this balance as they are frequent and often heterozygous. MicroRNAs bind the 3’UTR to inhibit translation of the messenger-RNA to protein. 3’UTR SNPs can alter microRNA binding and thereby alter inhibition of the allele on which they reside.

In the attached research article, we showed the first evidence for this mechanism in long QT syndrome: SNPs in the 3’UTR of the KCNQ1 gene repress translation by creating binding sites for a cardiac microRNA. These suppressive SNPs largely determined the severity of the long QT syndrome in carriers of a KCNQ1 mutation. When the suppressive SNPs reside on the normal KCNQ1 allele, the normal allele is repressed and there is clear clinical manifestation of the mutation. However, when the suppressive SNPs reside on the mutant KCNQ1 allele, this mutant allele is repressed and there are hardly clinical manifestations of the mutation.


These initial findings suggest that 3’UTR SNPs can alter microRNA binding and thereby modulate expression of a disease-causing mutation. This study uncovers a novel mechanism that explains why one single mutation can present such profound differences in disease severity. It is intriguing that our findings show that disease severity can be altered by the unaffected ‘married-in’ parent. ‘MicroRNAgenetics’ therefore become highly relevant and open novel ways to understand why genetic heart disease varies in its clinical manifestation.

Notes to editor

Presented by:  Dr. Ahmad S. Amin and Prof. Yigal M. Pinto
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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