Elevated serum gastrin levels in Jervell and Lange-Nielsen syndrome: A marker of severe KCNQ1 dysfunction?

Rice, Kathryn; Dickson, Graeme; Lane, M. R.; Crawford, Jackie; Chung, Seo‐Kyung; Rees, Mark I.; Shelling, Andrew N.; Love, Donald R.; Skinner, Jonathan R.

doi:10.1016/j.hrthm.2010.11.039

Cited by 27 publications

(23 citation statements)

References 32 publications

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“…However, a recent study showed that hypergastrinemia, a marker of parietal cell dysfunction, correlated well with QT c prolongation in KCNQ1 -linked Jervell and Lange-Nielsen Syndrome 32 . Interestingly, we previously found that even single-allele disruption of Kcne2 causes hypochlorhydria in mice, intermediate between wild-type mice and the achlorhydria we found in Kcne2 −/− mice 9 .…”

Section: Discussionmentioning

confidence: 97%

Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death

Kant

Anand

et al. 2014

Circ Cardiovasc Genet

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Background Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in diabetics. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia susceptibility genes - including the KCNE2 K+ channel β subunit - are expressed in multiple tissues, suggesting potential multiplex SCD substrates. Methods and Results Using “whole transcript” transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2−/− mouse pups, and adrenal remodeling consistent with metabolic syndrome in adult Kcne2−/− mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes, hypercholesterolemia, hyperkalemia, anemia and elevated angiotensin II. Kcne2 deletion was also prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately following transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia and atrioventricular block. Conclusions Disruption of a single, widely expressed arrhythmia susceptibility gene can generate a multisystem syndrome comprising manifold electrical and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.

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Section: Discussionmentioning

confidence: 97%

Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death

Kant

Anand

et al. 2014

Circ Cardiovasc Genet

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“…31, 32 Unfortunately, clinical data such as serum gastrin levels pertinent to these additional phenotypic manifestations were not available for the patients enrolled in this study. Thus, it remains to be seen if AR LQT1 patients are susceptible to similar hematologic and gastrointestinal pathologies as those described previously for JLNS.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Potential Genetic Determinants of Sensorineural Deafness in KCNQ1 Homozygosity and Compound Heterozygosity

Giudicessi

Ackerman

2013

Circ Cardiovasc Genet

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Background Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome (JLNS), a rare, autosomal recessive form of long QT syndrome (LQTS) characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. Here, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of LQTS patients. Methods and Results Retrospective analysis of all LQTS patients evaluated from July 1998 to April 2012 was used to identify those with ≥1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 patients (6.0%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 (73%) of these patients presented without the sensorineural deafness associated with JLNS. The degree of QT interval prolongation and number of breakthrough cardiac events were similar between cases with and without deafness. Interestingly, truncating mutations were more prevalent in JLNS (79%) than non-deaf cases (36%, p<0.001) derived from this study and those in the literature. Conclusions Here, we provide evidence that the “recessive” inheritance of a severe LQT1 phenotype in the absence of an auditory phenotype may represent a more common pattern of LQTS inheritance than previously anticipated and that these cases should be treated as a higher-risk LQTS subset similar to their JLNS counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ≥1 KCNQ1 mutation on each allele.

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“…The iPSC-CMs are created by somatic cells reprogramming into pluripotent stem cells using viral transduction or non-viral transfection or soluble proteins to introduce transcriptional factors to the somatic cell [85]. The resulting induced pluripotent stem cell can be differentiated specifically to induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) [86]. The iPSC-CMs can express encoded genes of the heart that might be absent in the original donor somatic cell.…”

Section: Decoding the Channelopathies' Mysteries Using Induced Pluripmentioning

confidence: 99%

Inherited Ventricular Arrhythmias, the Channelopathies and SCD: Current Knowledge and Future Speculations - Risk Stratification, Management Plans and Future Speculations

Abdulgader¹

2020

Sudden Cardiac Death

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Channelopathy constitutes significant proportion of SCD worldwide (around 10% or 370,000 deaths annually). It was creating a mysterious group of diseases until the second half of the last century when Anton Jervell and Fred Lange-Nielsen described Jervell Lange-Nielsen syndrome in 1957. It was late until 1995 where genetic characterization commenced. Later on, the massive genetic information with the discovery of genetic heterogeneity and allelic het¬erogeneity was a major victory in the field. The basic sciences in cellular electrophysiology and genetics complemented by meticulous clinical detection and the different clinical trials in the field opened a new era of wide therapeutic choices for clinicians. The knowledge obtained from the different experimental platforms especially the induced pluripotent stem cells is promising. The revolutionary move in SCD and channelopathies is described where correlation between the arrhythmogenesis and fluctuation in SGMA is established and must be investigated. The observation of the arrhythmogenicity of SGMA fluctuation and its effect on HRV together with the differential effect of certain sympathovagal tones (more sympathetic innervation is favoring VT/VF in LQTS1, LQTS2 and SQTS but not BrS or ERS) are all future directions to optimize our preventive, diagnostic as well as therapeutic options of SCD and channelopathy in humans.

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Elevated serum gastrin levels in Jervell and Lange-Nielsen syndrome: A marker of severe KCNQ1 dysfunction?

Cited by 27 publications

References 32 publications

Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death

Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death

Prevalence and Potential Genetic Determinants of Sensorineural Deafness in KCNQ1 Homozygosity and Compound Heterozygosity

Inherited Ventricular Arrhythmias, the Channelopathies and SCD: Current Knowledge and Future Speculations - Risk Stratification, Management Plans and Future Speculations

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