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http://purl.uniprot.org/citations/11889015http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/11889015http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/11889015http://www.w3.org/2000/01/rdf-schema#comment"

Background

Complex physiological interactions determine the functional consequences of gene abnormalities and make mechanistic interpretation of phenotypes extremely difficult. A recent example is a single mutation in the C terminus of the cardiac Na(+) channel, 1795insD. The mutation causes two distinct clinical syndromes, long QT (LQT) and Brugada, leading to life-threatening cardiac arrhythmias. Coexistence of these syndromes is seemingly paradoxical; LQT is associated with enhanced Na(+) channel function, and Brugada with reduced function.

Methods and results

Using a computational approach, we demonstrate that the 1795insD mutation exerts variable effects depending on the myocardial substrate. We develop Markov models of the wild-type and 1795insD cardiac Na(+) channels. By incorporating the models into a virtual transgenic cell, we elucidate the mechanism by which 1795insD differentially disrupts cellular electrical behavior in epicardial and midmyocardial cell types. We provide a cellular mechanistic basis for the ECG abnormalities observed in patients carrying the 1795insD gene mutation.

Conclusions

We demonstrate that the 1795insD mutation can cause both LQT and Brugada syndromes through interaction with the heterogeneous myocardium in a rate-dependent manner. The results highlight the complexity and multiplicity of genotype-phenotype relationships, and the usefulness of computational approaches in establishing a mechanistic link between genetic defects and functional abnormalities."xsd:string
http://purl.uniprot.org/citations/11889015http://purl.org/dc/terms/identifier"doi:10.1161/hc1002.105183"xsd:string
http://purl.uniprot.org/citations/11889015http://purl.org/dc/terms/identifier"doi:10.1161/hc1002.105183"xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/author"Clancy C.E."xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/author"Clancy C.E."xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/author"Rudy Y."xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/author"Rudy Y."xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/date"2002"xsd:gYear
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/date"2002"xsd:gYear
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/name"Circulation"xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/name"Circulation"xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/pages"1208-1213"xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/pages"1208-1213"xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/title"Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism."xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/title"Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism."xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/volume"105"xsd:string
http://purl.uniprot.org/citations/11889015http://purl.uniprot.org/core/volume"105"xsd:string
http://purl.uniprot.org/citations/11889015http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/11889015
http://purl.uniprot.org/citations/11889015http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/11889015
http://purl.uniprot.org/citations/11889015http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/11889015
http://purl.uniprot.org/citations/11889015http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/11889015
http://purl.uniprot.org/uniprot/Q14524http://purl.uniprot.org/core/citationhttp://purl.uniprot.org/citations/11889015
http://purl.uniprot.org/uniprot/Q14524#attribution-28625E4871A6B21CCA0D54391E202617http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/11889015
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