p.D1690N Nav1.5 rescues p.G1748D mutation gating defects in a compound heterozygous Brugada syndrome patient

Núñez, Lucı́a; Barana, Adriana; Amorós, Irene; Fuente, Marta González de la; Dolz-Gaitón, Pablo; Gómez, Ricardo; Rodríguez-García, Isabel; Mosquera, Ignacio; Monserrat, Lorenzo; Delpón, Eva; Caballero, Ricardo; Castro‐Beiras, Alfonso; Tamargo, Juan

doi:10.1016/j.hrthm.2012.10.025

Cited by 42 publications

(48 citation statements)

References 25 publications

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“…Also, disease-causing mutations of Brugada syndrome that cause spontaneous type I Brugada in some family members but only fever-induced Brugada in others have been described. 41 Thus, at the present time, patients with fever-induced type I Brugada pattern are considered to carry the disease.…”

Section: Discussionmentioning

confidence: 99%

Fever-induced Brugada pattern: How common is it and what does it mean?

Adler¹,

Topaz²,

Heller³

et al. 2013

Heart Rhythm

147

103

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BACKGROUND Fever is known to unmask the Brugada pattern on the electrocardiogram (ECG) and trigger ventricular arrhythmias in patients with Brugada syndrome. Genetic studies in selected cases with fever-induced Brugada pattern have identified disease-causing mutations. Thus, “fever-induced Brugada” is a recognized clinical entity. However, its prevalence has not been systematically evaluated. OBJECTIVE The purpose of this study was to assess the prevalence of Brugada pattern in consecutive patients with fever. METHODS ECGs of patients with fever admitted to the emergency department were evaluated for the presence of Brugada pattern and compared with ECGs of consecutive nonfebrile patients. RESULTS ECGs of 402 patients with fever and 909 without were evaluated. Type I Brugada pattern was 20 times more common in the febrile group than in the afebrile group (2% vs 0.1%, respectively, P = .0001). All patients with fever-induced type I Brugada pattern were asymptomatic and remained so during 30 months of follow-up. CONCLUSION Type I Brugada pattern is definitively more common among patients with fever, suggesting that asymptomatic Brugada syndrome is more prevalent than previously estimated.

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Section: Discussionmentioning

confidence: 99%

Fever-induced Brugada pattern: How common is it and what does it mean?

Adler¹,

Topaz²,

Heller³

et al. 2013

Heart Rhythm

147

103

View full text Add to dashboard Cite

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“…Both mutations reduced the peak Na + current density due to limited trafficking of the SCN5A protein towards the membrane, but Gly1748Asp also profoundly affected channel gating. The His558Arg polymorphism was found to be capable of rescuing the defective trafficking of SCN5A Asn1690 towards the membrane when present in cis to the pathological lesion (Núñez et al 2013). Intriguingly, cotransfection with Asn1690, either alone or together with the modulatory His558Arg polymorphism, completely restored the gating defect associated with the pathogenic Gly1748Asp mutation in trans , although it only slightly rescued its trafficking.…”

Section: Modulating Influence Of Additional Allelic Variants In Cis Omentioning

confidence: 99%

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

et al. 2013

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Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.

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“…Surprisingly, cotransfection with p.D1690N, either alone or together with the polymorphism (p.H558R-D1690N), completely restored the profound gating defects exhibited by p.G1748D channels but only slightly rescued their trafficking. 35 The common variant H558R can also restore the sodium current in carriers of an R282H SCN5A mutation 36 and seems to be a genetic modulator of BrS among carriers of an SCN5A mutation, in whom the presence of the less common allele G improves the electrocardiographic characteristics and clinical phenotype. 37 …”

Section: Clinical Characteristics Of Patients With Brugada Syndrome Cmentioning

confidence: 99%