KCNE2 – Long QT Syndrome

KCNE2 encodes MiRP1, a β‐subunit modulating the rapid delayed rectifier current (IKr) conducted by the hERG channel. Pathogenic variants in KCNE2 cause the autosomal-dominant LQT6 subtype of congenital long QT syndrome (LQTS), characterized by prolonged ventricular repolarization and risk of torsades de pointes.

Early genetic screens in 40 unrelated LQTS patients detected no KCNE2 mutations, suggesting rare involvement in monogenic LQTS (PMID:11468227). A single case report described digenic inheritance of LQT2 (KCNH2) and LQT6 (KCNE2) in a 37-year-old woman with ventricular fibrillation and QTc prolongation (PMID:31320904). More comprehensive analysis of 150 unrelated LQTS patients identified one novel KCNE2 variant, NM_172201.2:c.193G>A (p.Val65Met), in a 17-year-old female with syncope (PMID:12185453). No segregation data are available, and affected relatives are not reported.

KCNE2 variants show autosomal-dominant inheritance with incomplete penetrance. Segregation analysis is limited: no additional affected relatives with segregating KCNE2 variants have been documented.

Functional studies corroborate KCNE2’s role in repolarization. The p.Val65Met substitution co-expressed with hERG accelerates inactivation kinetics in CHO cells, reducing IKr. Targeted deletion of kcne2 in mice decreases I(K,slow1) by 50% and I(to) by 25%, prolonging ventricular action potential duration and QTc under anesthesia (PMID:18603586). These data support a loss-of-function mechanism.

Conflicting evidence arises from high KCNE2 variant frequencies in healthy cohorts (e.g., p.Thr8Ala and p.Met54Val present in 1–4% of individuals), raising the possibility that many KCNE2 changes are benign polymorphisms requiring secondary provocation for phenotypic expression.

Integration of genetic and functional evidence indicates a Limited gene–disease association for KCNE2 and LQTS. While KCNE2 variants can modulate IKr and, in rare cases, contribute to LQTS phenotypes, most KCNE2 alterations likely act as susceptibility factors rather than primary monogenic causes. Key take-home: KCNE2 sequencing may be informative in unexplained or digenic LQTS but should be interpreted with caution alongside primary LQTS genes and functional data.

References

• Case reports in medicine • 2019 • A Rare Case of the Digenic Inheritance of Long QT Syndrome Type 2 and Type 6 PMID:31320904
• Clinical chemistry • 2001 • Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome PMID:11468227
• FASEB journal • 2008 • Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f) PMID:18603586
• Journal of molecular medicine (Berlin, Germany) • 2002 • Identification and functional characterization of a novel KCNE2 (MiRP1) mutation that alters HERG channel kinetics PMID:12185453

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