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Single nucleotide deletion mutation of KCNH2 gene is responsible for LQT syndrome in a 3-generation Korean family.

ABSTRACT: Long QT syndrome (LQTS) is characterized by the prolongation of the QT interval in ECG and manifests predisposition to life threatening arrhythmia which often leads to sudden cardiac death. We encountered a 3-generation family with 5 affected family members in which LQTS was inherited in autosomal dominant manner. The LQTS is considered an ion channel disorder in which the type and location of the genetic mutation determines to a large extent the expression of the clinical syndrome. Upon screening of the genomic sequences of cardiac potassium ion channel genes, we found a single nucleotide C deletion mutation in the exon 3 of KCNH2 gene that co-segregates with the LQTS in this family. This mutation presumably resulted in a frameshift mutation, P151fs+15X. This study added a new genetic cause to the pool of mutations that lead to defected potassium ion channels in the heart.

SUBMITTER: Park JK

PROVIDER: S-EPMC3763117 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Single nucleotide deletion mutation of KCNH2 gene is responsible for LQT syndrome in a 3-generation Korean family.

Park Jong Keun JK Oh Yong-Seog YS Choi Jee-hyun JH Yoon Sungjoo Kim SK

Journal of Korean medical science 20130828 9

Long QT syndrome (LQTS) is characterized by the prolongation of the QT interval in ECG and manifests predisposition to life threatening arrhythmia which often leads to sudden cardiac death. We encountered a 3-generation family with 5 affected family members in which LQTS was inherited in autosomal dominant manner. The LQTS is considered an ion channel disorder in which the type and location of the genetic mutation determines to a large extent the expression of the clinical syndrome. Upon screeni ...[more]

PMID: 24015048

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Project description:Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Clinical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ1dup12; p.R360_Q361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LQT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ1dup12 mutation for the LQT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LQTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LQT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures.

Dataset Information

Single nucleotide deletion mutation of KCNH2 gene is responsible for LQT syndrome in a 3-generation Korean family.

Publications

Single nucleotide deletion mutation of KCNH2 gene is responsible for LQT syndrome in a 3-generation Korean family.

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