Key result
KCNQ1 mutations delV595 and P631fs/19 impaired cell surface expression due to trafficking defects, severely affecting outward potassium currents without apparent dominant negative effects.
Identifies novel trafficking defect mechanisms for KCNQ1 mutations in autosomal-recessive Long QT syndrome, providing new insights into the molecular basis of the disease.
May open avenues for trafficking-targeted therapies in recessive LQTS; leaves open translation to patient care.
Long QT syndrome (LQTS) is a hereditary arrhythmia caused by mutations in genes for cardiac ion channels, including a potassium channel, KvLQT1. Inheritance of LQTS is usually autosomal-dominant, but autosomal-recessive inheritance can be observed in patients with LQTS accompanied by hearing loss. In this study, we investigated the functional alterations caused by KCNQ1 mutations, a deletion (delV595) and a frameshift (P631fs/19), which were identified in compound heterozygous state in two patients with autosomal-recessive LQTS not accompanied by hearing loss. Functional analyses showed that both mutations impaired cell surface expression due to trafficking defects. The mutations severely affected outward potassium currents without apparent dominant negative effects. It was found that delV595 impaired subunit binding, whereas P631fs/19 was retained in endoplasmic reticulum due to the newly added 19-amino acid sequence containing two retention motifs (R(633)GR and R(646)LR). This is the first report of novel mechanisms for trafficking abnormality of cardiac ion channels, providing us new insights into the molecular mechanisms of LQTS.
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Sato et al. (2009) studied Autosomal-recessive Long QT Syndrome (LQTS) (n=2). KCNQ1 mutations (delV595 and P631fs/19) was evaluated on Functional alterations (cell surface expression and outward potassium currents). KCNQ1 mutations delV595 and P631fs/19 impaired cell surface expression due to trafficking defects, severely affecting outward potassium currents without apparent dominant negative effects.
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