title: A novel mutation in human ether-a-go-go-related gene, alanine to proline at position 490, found in a large family with autosomal dominant long QT syndrome.
abstract: Long-QT syndrome is a rare disease characterized by prolonged ventricular repolarization. The clinical presentation of long-QT syndrome is the occurrence of syncope, seizures, or cardiac arrest in young patients. Previous studies have demonstrated locus heterogeneity, with causative mutations reported in >or=8 different genes, including the human ether-a-go-go-related gene. This study was conducted in 26 members of a 4-generation family with long-QT syndrome. The proband was a 14-year-old female patient referred to the emergency department for the evaluation of recurrent syncope associated with a prolonged QT interval on electrocardiography at rest. There was a family history of sudden death in a 27-year-old woman. Sequencing of the entire coding regions of the human ether-a-go-go-related gene and the intron and exon boundaries of the proband identified a single base-pair substitution (guanine to cytosine at nucleotide 1468). This mutation resulted in a novel missense mutation, alanine to proline at position 490 (Ala490Pro), in the inner loop of the S2 and S3 domains. The proband was heterozygous for the Ala490Pro mutation. To address whether the mutational change detected in the patient would be a polymorphism, 100 control subjects from the same ethnical background were investigated. None showed the Ala490Pro substitution. Of 26 family members, 9 were mutation carriers, and none had normal electrocardiographic results. The penetrance of this pedigree was assumed to be 100%. In conclusion, the Ala490Pro mutation of the human ether-a-go-go-related gene is a rare, novel mutation that was inherited in this family, leading to Romano-Ward syndrome with complete penetrance.
authors.affiliation: Cardiology Department, University of Foggia, Foggia, Italy. pierluigipel@yahoo.it
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Pellegrino
authors.forename: Valeria
authors.initials: V
authors.lastname: Bafunno
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ieva
authors.forename: Natale Daniele
authors.initials: ND
authors.lastname: Brunetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mavilio
authors.forename: Francesco
authors.initials: F
authors.lastname: Sessa
authors.forename: Massimo
authors.initials: M
authors.lastname: Grimaldi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Margaglione
authors.forename: Matteo
authors.initials: M
authors.lastname: Di Biase
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000235:genetics; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D011392:Proline / Q000235:genetics; D029597:Romano-Ward Syndrome / Q000235:genetics*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011392:Proline; D000409:Alanine