Pub Date : 2011-10-25DOI: 10.4081/cardiogenetics.2011.e13
Jianding Cheng, David W Van Norstrand, Argelia Medeiros-Domingo, David J Tester, Carmen R Valdivia, Bi-Hua Tan, Matteo Vatta, Jonathan C Makielski, Michael J Ackerman
The SNTA1-encoded α1-syntrophin (SNTA1) missense mutation, p.A257G, causes long QT syndrome (LQTS) by pathogenic accentuation of Nav1.5's sodium current (INa). Subsequently, we found p.A257G in combination with the SNTA1 polymorphism, p.P74L in 4 victims of sudden infant death syndrome (SIDS) as well as in 3 adult controls. We hypothesized that p.P74L-SNTA1 could functionally modify the pathogenic phenotype of p.A257G-SNTA1, thus explaining its occurrence in non-LQTS populations. The SNTA1 variants p.P74L, p.A257G, and the combination variant p.P74L/p.A257G were engineered using PCR-based overlap-extension and were co-expressed heterologously with SCN5A in HEK293 cells. INa was recorded using the whole-cell method. Compared to wild-type (WT), the significant increase in peak INa and window current found with p.A257G was reversed by the intragenic variant p.P74L (p.P74L/p.A257G). These results report for the first time the intragenic rescue of an LQT-associated SNTA1 mutation when found in combination with the SNTA1 polymorphism p.P74L, suggesting an ever-increasing picture of complexity in terms of genetic risk stratification for arrhythmia.
{"title":"LQTS-associated mutation A257G in α1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype.","authors":"Jianding Cheng, David W Van Norstrand, Argelia Medeiros-Domingo, David J Tester, Carmen R Valdivia, Bi-Hua Tan, Matteo Vatta, Jonathan C Makielski, Michael J Ackerman","doi":"10.4081/cardiogenetics.2011.e13","DOIUrl":"https://doi.org/10.4081/cardiogenetics.2011.e13","url":null,"abstract":"<p><p>The <i>SNTA1</i>-encoded α1-syntrophin (SNTA1) missense mutation, p.A257G, causes long QT syndrome (LQTS) by pathogenic accentuation of Nav1.5's sodium current (<i>I</i><sub>Na</sub>). Subsequently, we found p.A257G in combination with the SNTA1 polymorphism, p.P74L in 4 victims of sudden infant death syndrome (SIDS) as well as in 3 adult controls. We hypothesized that p.P74L-SNTA1 could functionally modify the pathogenic phenotype of p.A257G-SNTA1, thus explaining its occurrence in non-LQTS populations. The SNTA1 variants p.P74L, p.A257G, and the combination variant p.P74L/p.A257G were engineered using PCR-based overlap-extension and were co-expressed heterologously with SCN5A in HEK293 cells. <i>I</i><sub>Na</sub> was recorded using the whole-cell method. Compared to wild-type (WT), the significant increase in peak <i>I</i><sub>Na</sub> and window current found with p.A257G was reversed by the intragenic variant p.P74L (p.P74L/p.A257G). These results report for the first time the intragenic rescue of an LQT-associated SNTA1 mutation when found in combination with the SNTA1 polymorphism p.P74L, suggesting an ever-increasing picture of complexity in terms of genetic risk stratification for arrhythmia.</p>","PeriodicalId":41330,"journal":{"name":"Cardiogenetics","volume":"1 1","pages":""},"PeriodicalIF":0.6,"publicationDate":"2011-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4081/cardiogenetics.2011.e13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31938432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-08-22DOI: 10.4081/cardiogenetics.2011.e10
Quinn S Wells, Natalie L Ausborn, Birgit H Funke, Jean P Pfotenhauer, Joseph L Fredi, Samantha Baxter, Thomas D Disalvo, Charles C Hong
Idiopathic dilated cardiomyopathy (DCM) is a primary myocardial disorder characterized by ventricular chamber enlargement and systolic dysfunction. Twenty to fifty percent of idiopathic DCM cases are thought to have a genetic cause. Of more than 30 genes known to be associated with DCM, rare variants in the VCL and MYBPC3 genes have been reported in several cases of DCM. In this report, we describe a family with DCM and congenital abnormalities who carry a novel missense mutation in the VCL gene. More severely affected family members also possess a second missense variant in MYBPC3, raising the possibility that this variant may be a disease modifier. Interestingly, many of the affected individuals also have congenital defects, including two with bicuspid aortic valve with aortic regurgitation. We discuss the implications of the family history and genetic information on management of at-risk individuals with aortic regurgitation.
{"title":"Familial dilated cardiomyopathy associated with congenital defects in the setting of a novel VCL mutation (Lys815Arg) in conjunction with a known MYPBC3 variant.","authors":"Quinn S Wells, Natalie L Ausborn, Birgit H Funke, Jean P Pfotenhauer, Joseph L Fredi, Samantha Baxter, Thomas D Disalvo, Charles C Hong","doi":"10.4081/cardiogenetics.2011.e10","DOIUrl":"https://doi.org/10.4081/cardiogenetics.2011.e10","url":null,"abstract":"<p><p>Idiopathic dilated cardiomyopathy (DCM) is a primary myocardial disorder characterized by ventricular chamber enlargement and systolic dysfunction. Twenty to fifty percent of idiopathic DCM cases are thought to have a genetic cause. Of more than 30 genes known to be associated with DCM, rare variants in the <i>VCL</i> and <i>MYBPC3</i> genes have been reported in several cases of DCM. In this report, we describe a family with DCM and congenital abnormalities who carry a novel missense mutation in the <i>VCL</i> gene. More severely affected family members also possess a second missense variant in <i>MYBPC3</i>, raising the possibility that this variant may be a disease modifier. Interestingly, many of the affected individuals also have congenital defects, including two with bicuspid aortic valve with aortic regurgitation. We discuss the implications of the family history and genetic information on management of at-risk individuals with aortic regurgitation.</p>","PeriodicalId":41330,"journal":{"name":"Cardiogenetics","volume":"1 1","pages":""},"PeriodicalIF":0.6,"publicationDate":"2011-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4081/cardiogenetics.2011.e10","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31757004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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