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

Amin, Ahmad S.; Giudicessi, John R.; Tijsen, Anke J.; Spanjaart, Anne M.; Reckman, Yolan J.; Klemens, Christine A.; Tanck, Michael W.T.; Kapplinger, Jamie D.; Hofman, Nynke; Sinner, Moritz F.; Müller, Martina; Wijnen, Wino J.; Tan, Hanno L.; Bezzina, Connie R.; Creemers, Esther E.; Wilde, Arthur A.M.; Ackerman, Michael J.; Pinto, Yigal M.

doi:10.1093/eurheartj/ehr473

Cited by 131 publications

(88 citation statements)

References 16 publications

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“…An overview of known miRNAs affecting cardiac potassium currents is given in Adding another level of complexity, Amin et al (12) reported that common variants in the 3'-UTR of the KCNQ1 gene encoding K V 7.1 modified disease severity in LQTS patients in an allele-specific manner. As K V 7.1 channels are composed of tetramers, in a heterozygous mutation carrier channels will be formed from two healthy and two mutant subunits, provided that wild-type and mutant alleles are expressed equally well.…”

Section: Posttranscriptional Mechanismsmentioning

confidence: 99%

“…Depending on which nucleotide sequence favors the binding of miRNAs, then the balance of wild-type and mutant subunits relies on whether the "suppressive" SNP variants reside on the normal or mutant allele. Accordingly, an increased expression of the mutant allele would enhance the disease phenotype of the patient, while an increased expression of the wild-type allele could possibly result in an asymptomatic phenotype (12).…”

Section: Posttranscriptional Mechanismsmentioning

confidence: 99%

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Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

196

197

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About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K+ channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K+ channels drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K+ channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and posttranslational remodeling of the individual K+ channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry arrhythmia.

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Section: Posttranscriptional Mechanismsmentioning

confidence: 99%

Section: Posttranscriptional Mechanismsmentioning

confidence: 99%

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

196

197

View full text Add to dashboard Cite

show abstract

“…), and is associated with various physiological functions (cardiocyte repolarization, gastric acidification, electrolyte excretion/reabsorption, etc.) (Schroeder et al, 2000;Vallon et al, 2001Vallon et al, , 2005Warth et al, 2002;Lang et al, 2007;Yang et al, 2007;Das et al, 2009;Pan et al, 2010;Amin et al, 2012;Sung et al, 2014). In the mouse kidney, KCNQ1 mRNA is expressed in the PT, DCT, CNT, CD, and glomeruli (Wang, 2004;Zheng et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, mutations in the KCNQ1 gene have been associated with human Romano-Ward or long QT syndrome (OMIM: No. 192500) (Amin et al, 2012), Jervell and Lange-Nielsen syndrome (OMIM: No. 220400) (Sung et al, 2014), familial atrial fibrillation (Das et al, 2009), and atrioventricular block (Yang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

KCNQ1 A340E impairs electrolyte homeostasis independently of the renin-angiotensin-aldosterone system in mice

et al. 2016

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ABSTRACT. KCNQ1 (KvLQT1) is the pore-forming a-subunit of the potassium channel. To uncover its role in electrolyte metabolism, we investigated the effects of KCNQ1 A340E, a loss-of-function mutant, on J343 mice. Compared with the normal controls (C57BL/6J mice) bearing the wild-type KCNQ1 gene, J343 mice bearing KCNQ1 A340E demonstrated a much higher 24-h intake of electrolytes (potassium, sodium, and chloride). However, they suffered from significant electrolyte loss through both the feces and urine during a period of 24 h. Unbalance in electrolyte metabolism disrupted the electrolyte homeostasis in the J343 mice, which was characterized by the comparatively lower level of serum potassium (J343 vs C57BL/6J: 12.06 ± 1.47 vs 14.44 ± 3.58 mM, P = 0.01) and higher levels of serum sodium (J343 vs C57BL/6J: 148.05 ± 4.47 vs 115.15 ± 17.25 mM, P = 4.20 x 10 -4 ) and chloride (J343 vs C57BL/6J: 118.0 ± 4.47 vs 85.21 ± 11.90 mM, P = 2.47 x 10 -5 ). Between the J343 and C57BL/6J mice, there was no statistically significant difference in KCNQ1 expression in the gastrointestinal tract and kidney. Normal concentrations of plasma renin, angiotensin I, and aldosterone were also detected in both lines of mice. KCNQ1, therefore, is suggested to play a central role in electrolyte metabolism. KCNQ1 A340E, with the loss-of-function phenotype, may dysregulate electrolyte homeostasis in mice independently of the activity of the renin-angiotensin-aldosterone system.

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“…The 5′-flanking region of the gene, particularly the minimal promoter, is the key transcriptional regulatory region in gene expression (Saeki et al 2011, Amin et al 2012. SNPs in the promoter region may modify the transcription factor binding sites, thereby affecting gene expression (Pan et al 2013, Zhang et al 2015.…”

Section: Introductionmentioning

confidence: 99%

A g.-1256 A>C in the promoter region of CAPN1 is associated with semen quality traits in Chinese Holstein bulls

Cui¹,

Sun²,

Wang

et al. 2016

Reproduction

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The micromolar calcium-activated neutral protease gene (CAPN1) is a physiological candidate gene for sperm motility. However, the molecular mechanisms involved in regulating the expression of the CAPN1 gene in bulls remain unknown. In this study, we investigated the expression pattern of CAPN1 in testis, epididymis, and sperm at the RNA and protein levels by qRT-PCR, western blot, immunohistochemistry, and immunofluorescence assay. Results revealed that the expression of CAPN1 levels was higher in the sperm head compared with that in other tissues. Moreover, we identified a novel single-nucleotide polymorphism (g.-1256 A>C, ss 1917715340) in the noncanonical core promoter of the CAPN1 gene between base g.-1306 and g.-1012. Additionally, we observed greater sperm motility in bulls with the genotype CC than in those with the genotype AA (P<0.01), indicating that different genotypes were associated with the bovine semen trait. Furthermore, a higher fluorescence intensity of the C allele than that of the A allele at g. -1256 A>C was revealed by transient transfection in MLTC-1 cells and luciferase report assay. Finally, CAPN1 was highly expressed in the spermatozoa with the CC genotype compared with that with the AA genotype by qRT-PCR. This study is the first report on genetic variant g.-1256 A>C in the promoter region of CAPN1 gene association with the semen quality of Chinese Holstein bulls by influencing its expression. g.-1256 A>C can be a functional molecular marker in cattle breeding.

show abstract

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

Cited by 131 publications

References 16 publications

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

KCNQ1 A340E impairs electrolyte homeostasis independently of the renin-angiotensin-aldosterone system in mice

A g.-1256 A>C in the promoter region of CAPN1 is associated with semen quality traits in Chinese Holstein bulls

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