The KCNQ1 gene maps to chromosome 11p15.5-p15.4. It is expressed in several tissues throughout the body, such as the kidneys, lungs, stomach, and intestine. The KCNQ1 gene encodes the pore-forming subunit of a voltage-gated K+ channel (KvLQT1) that plays a key role in shaping the cardiac action potential as well as in controlling the water and salt homeostasis in several epithelial tissues. KCNQ1 channels in these tissues are tightly regulated by auxiliary proteins and accessory factors, capable of modulating the properties of the channel complexes.
Defects in these channels are the cause of familial atrial fibrillation, Jervell and Lange-Nielsen syndrome, Romano-Ward syndrome, short QT syndrome, and other diseases. The long QT syndrome (LQTS) is a heart disorder characterized by several symptoms including polymorphic ventricular arrhythmia known as "torsade de points" and ventricular fibrillation, sometimes leading to syncope or sudden death.
The KCNQ1 gene consists of 16 coding exons, and spans approximately 404 kb in the genomic DNA. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. At least 500 different mutations have been identified in the KCNQ1 gene in patients with Romano-Ward syndrome. These mutations cause reduction in the potassium ion transport out of cardiac muscle cells that alters the transmission of electrical signals in the heart, increasing the risk of an irregular heartbeat that can cause syncope or sudden death.
Bhuiyan et al. (2008) studied two consanguineous Arabian families with history of sudden death of several children. None of the affected had any evidence of hearing impairment. Homozygosity mapping and molecular analysis identified a novel homozygous splice acceptor site mutation in intron-1 (c.387-5T>A) of the KCNQ1 gene in the affected patients of both families. RNA analysis showed that the mutation caused transcriptional aberration, but leaving 10% of the normal allele transcript intact. This 10% was found to be enough to maintain hearing function, but not sufficient to maintain cardiac repolarization within normal limits. The fact that the two families were unrelated prompted Bhuiyan et al. (2008) to consider that this was likely to be a founder mutation in the southern province of Saudi Arabia. Later, Bhuiyan et al. (2009) performed genetic analysis for six Saudi families affected with long QT syndrome. Two of these families had patients affected with long QT syndrome 1 and four had long QT syndrome 2. Entire coding exons of the genes KCNQ1, KCNH2, and SCN5A were sequenced. A novel homozygous (c.387-5 T>A) mutation was identified within intron 1 of the KCNQ1 gene 5-nucleotide upstream from the first nucleotide of exon-2, in the probands of both the families with LQTS 1, whose parents were heterozygous for the mutation. Both families originated from the Assir region, although they were not knowingly related. Haplotype analyses lend credence to the theory that mutations in both families originated from the same ancestor.
Shinwari et al. (2013) studied a large Saudi family with Long QT Syndrome. Of the 26 members in this family who underwent assessment, only two were clinically symptomatic. However, gene sequencing identified a novel heterozygous c.773A>C (p.His258Pro) mutation in 12 family members. This mutation was not found in 100 chromosomes from ethnically matched normal controls. The Histidine residue affected by this mutation is highly conserved, and both SIFT and Polyphen programs predicted the mutation to be 'probably intolerant' and 'probably damaging'. The family showed a clear intrafamilial variability in the phenotype. The mutation showed incomplete penetrance, with individuals carrying it ranging from being asymptomatic to having episodes that required ICD.
Al-Aama et al. (2014) demonstrated for the first time that Jervell and Lange-Nielsen syndrome could also occur due to a spontaneous de novo mutation in the KCNQ1 gene in the affected individual, not inherited from the parent. The proband was a 5-year-old girl. At birth, a 12-lead ECG was recorded and she was diagnosed to have LQTS. Sequencing of the KCNQ1 gene detected compound heterozygous mutations, c.820_c.830del (exon 6) and c.1251+1G>T (splice site of exon-intron 9). Genetic screening of both parents showed that the proband had inherited the mutation, c.820_c.830del, from her mother. However, the second mutation, c.1251+1G>T, was present neither in the mother nor in the father. Paternity test based on microsatellite repeat length analysis excluded any non-paternity. Haplotype analysis with five closely spaced microsatellite repeat polymorphic markers encompassing the KCNQ1 gene confirmed paternal inheritance of the second allele, which was not mutated in the father. The proband has two brothers and two sisters; one brother and one sister are also heterozygous carriers for the mutation c.820_c.830del. None of the four siblings of the proband are carriers of the second mutation c.1251+1G>T. In a more comprehensive study, Al-Aama et al. (2015) presented the cases of six families with at least one JLNS-affected member and who presented between 2011 and 2013. Pathogenic mutations in the KCNQ1 gene were detected in all JLNS patients. The homozygous mutations detected were p.Leu273Phe, p.Asp202Asn, p.Ile567Thr, and c.1486_1487delCT and compound heterozygous mutations were c.820_ 830del and c.1251+1G>T. All living JLNS patients except one had a QTc of >500?ms and a history of recurrent syncope. ?-Blockers abolished the cardiac-related events in all patients except two siblings with homozygous p.Ile567Thr mutation. Four of the six mutations were originally reported in autosomal dominant long QT syndrome (LQTS) patients. Eighty percent of the heterozygote mutation carriers showed prolongation of QTc, but majority of these reported no symptoms attributable to arrhythmias.
Turki et al. (2012) investigated the association of rs231361, rs231359, rs151290, rs2237892, rs2283228, rs2237895, and rs2237896 KCNQ1 polymorphisms with type 2 diabetes (T2DM) in 900 Tunisian patients and 600 normoglycemic controls. Minor allele frequency (MAF) of the seven tested KCNQ1 variants was comparable between T2DM cases and controls. Mild association of rs2237892 genotypes with T2DM was seen (P=0.014), highlighted by the significant association of the C/T genotype with increased T2DM risk (OR, 2.11; 95%CI, 1.25-3.53), after adjusting for BMI, gender, systolic and diastolic blood pressure, and serum lipid profile. Heterogeneity in linkage disequilibrium pattern between tested KCNQ1 variants analyzed was seen. Two-locus (rs231361 and rs231359) and 5-locus (remaining five SNPs) haplotype analysis did not reveal any significant association with any of the haplotypes contained in either block 1 or block 2.
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