Murai and colleagues (1989) first cloned the KCNE1 gene that was predicted to encode a novel human membrane protein with a selective potassium permeation by membrane depolarization. The KCNE1 deduced protein that was also named minK (‘minimum potassium ion channel’; Lai and colleagues (1994)) has an estimated weight of only 13.9 kD and consists of 129 amino acid residues and shares structural characteristics and extensive homology with the rat counterpart. Through co-transfection studies with human KCNE1 and KCNQ1 cRNAs (LQT1), Sanguinetti and colleagues (1996) demonstrated that both proteins, KVLQT1 and minK, co-assemble to form the slowly acrtivating component I(Ks) of the cardiac delayed rectifier channel. Independently, Barhanin and colleagues (1996) expressed mouse KVLQT1 in COS cells and demonstrated that also minK was required to form the I(Ks) channel. Moreover, McDonald and co-workers (1997) showed that minK was able to form a stable complex with HERG protein (LQT2) and that this heteromultimerization regulates the rapidly activating component I(Kr) of cardiac delayed rectifier. Taken together, minK, through the formation of heteromeric channel complexes, has a central to the control of the heart rate and rhythm.

Chevillard et al. (1993) mapped KCNE1 by somatic cell hybridization and further regionalized to 21q22.1-q22.2 by isotopic in-situ hybridization. Later, Malo et al. (1995) mapped the KCNE1 gene by PCR analysis in two complete panels of human/rodent hybrid DNA to chromosome 21 with 100% concordance, and sublocalized the gene again to 21q22.1-q22.2 using this approach.

A putative role of KCNE1 in inherited arrhythmias was proposed before the precise protein function of minK was known. In a segregation analysis with a gene polymorphism (S38G), Lai et al. (1994) were unable to define genetic linkage in patients with inherited (autosomal dominant) LQT syndrome. Tesson et al. (1996) also excluded the KCNE1 gene as the site of the mutation in the Jervell and Lange-Nielsen syndrome (JLNS; autosomal recessive LQT syndrome with congenital deafness) in 4 consanguineous families using a cosegregation approach with nearby microsatellite and intragenic polymophic markers. Subsequently, mutations in the KCNQ1 gene were identified in their families with JLNS (Neyroud and colleagues (1997)). In contrast, Schulze-Bahr and co-workers (1997) excluded this gene in a large Lebanese family with three affected siblings with JLNS. Three of 6 children had prolonged QT intervals and congenital bilateral deafness; 2 of the 3 had suffered from recurrent syncope since early childhood. Both parents and the 3 other sibs showed normal hearing and had QT durations within the normal range. In further investigations, compound heterozygous mutations in the KCNE1 gene were found in the three JLNS patients; all other family members were heterozygous for one of the mutations, but clinically unaffected. Independently, Splawski et al. (1997) defined KCNE1 missense mutations in affected members of two LQT families with an autosomal dominant inheritance. Interestingly, heterozygous carriers of the D76N mutation were symptomatic in the study of Splawski et al. (1997), whereas not in the case reports of Schulze-Bahr et al. (1997) and Duggal et al. (1997). Thus, also for KCNE1 mutations – like for the KCNQ1 gene – a variable clinical expressivity may be found and raises the queston of disease-modifying or triggering factors.

Bianchi et al. (1999) used electrophysiologic and immunocytochemical methods to determine the cellular phenotypes of four LQT5 mutants when coexpressed with KCNQ1 (in Xenopus oocytes) or with HERG (in HEK293 cells). Four different missense mutations previously identified in patients with LQT syndrome were expressed. One mutation, L51H, probably exhibit an intracellular trafficking transport, whereas two mutations (V47F and W87R) displayed an altered channel gating and reduced I(Ks) amplitudes. In addition to effects on I(Ks), V47F increased I(Kr) (HERG) current but to a lesser extent than wildtype minK and, in contrast, D76N suppressed I(Kr) current markedly. The different mutant minK proteins interacted with both, KVLQT1 and HERG protein, and modify the expression of I(Ks) and I(Kr) current.

Overall, KCNE1 mutations are relatively unfrequent among LQTS since they represent approximately 1.0-1.5% of genotyped patients.

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