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High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.


ABSTRACT:

Background

KCNE1 encodes a 129-residue cardiac potassium channel (IKs) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility.

Results

Here, we demonstrate the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein coding KCNE1 variants. We comprehensively assayed KCNE1 variant cell surface expression (2,554/2,709 possible single amino acid variants) and function (2,539 variants). We identified 470 loss-of-surface expression and 588 loss-of-function variants. Out of the 588 loss-of-function variants, only 155 had low cell surface expression. The latter half of the protein is dispensable for protein trafficking but essential for channel function. 22 of the 30 KCNE1 residues (73%) highly intolerant of variation were in predicted close contact with binding partners KCNQ1 or calmodulin. Our data were highly concordant with gold standard electrophysiological data (ρ = -0.65), population and patient cohorts (32/38 concordant variants), and computational metrics (ρ = -0.55). Our data provide moderate-strength evidence for the ACMG/AMP functional criteria for benign and pathogenic variants.

Conclusions

Comprehensive variant effect maps of KCNE1 can both provide insight into IKs channel biology and help reclassify variants of uncertain significance.

SUBMITTER: Muhammad A 

PROVIDER: S-EPMC10168370 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

High-throughput functional mapping of variants in an arrhythmia gene, <i>KCNE1</i>, reveals novel biology.

Muhammad Ayesha A   Calandranis Maria E ME   Li Bian B   Yang Tao T   Blackwell Daniel J DJ   Harvey M Lorena ML   Smith Jeremy E JE   Chew Ashli E AE   Capra John A JA   Matreyek Kenneth A KA   Fowler Douglas M DM   Roden Dan M DM   Glazer Andrew M AM  

bioRxiv : the preprint server for biology 20230429


<h4>Background</h4><i>KCNE1</i> encodes a 129-residue cardiac potassium channel (I<sub>Ks</sub>) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility.<h4>Results</h4>Here, we demonstrate the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein coding KCNE1 v  ...[more]

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