A novel KCNJ2 nonsense mutation, S369X, impedes trafficking and causes a limited form of Andersen-Tawil syndrome
| Autor: | Takeru Makiyama, Yoshisumi Haruna, Masaharu Akao, Seiko Ohno, Keiko Tsuji, Takahiro Doi, Takeshi Morimoto, Takeshi Kimura, Yoshiaki Takahashi, M. Horie |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Patch-Clamp Techniques Adolescent Ventricular Tachyarrhythmias Long QT syndrome Recombinant Fusion Proteins Nonsense mutation Molecular Sequence Data CHO Cells QT interval Electrocardiography Andersen–Tawil syndrome Cricetulus Internal medicine Cricetinae Chlorocebus aethiops Genetics medicine Fluorescence Resonance Energy Transfer Animals Humans Amino Acid Sequence Potassium Channels Inwardly Rectifying Genetics (clinical) Andersen Syndrome Inward-rectifier potassium ion channel business.industry Periodic paralysis medicine.disease Pedigree Protein Transport Endocrinology Codon Nonsense Mutation (genetic algorithm) COS Cells Cardiology and Cardiovascular Medicine business Sequence Alignment |
| Zdroj: | Circulation. Cardiovascular genetics. 4(3) |
| ISSN: | 1942-3268 |
| Popis: | Background— Mutations in KCNJ2 , a gene encoding the inward rectifier K + channel Kir2.1, are associated with Andersen-Tawil syndrome (ATS), which is characterized by (1) ventricular tachyarrhythmias associated with QT (QU)-interval prolongation, (2) periodic paralysis, and (3) dysmorphic features. Methods and Results— We identified a novel KCNJ2 mutation, S369X, in a 13-year-old boy with prominent QU-interval prolongation and mild periodic paralysis. The mutation results in the truncation at the middle of the cytoplasmic C-terminal domain that eliminates the endoplasmic reticulum (ER)-to-Golgi export signal. Current recordings from Chinese hamster ovary cells transfected with KCNJ2 -S369X exhibited significantly smaller K + currents compared with KCNJ2 wild type (WT) (1 μg each) (−84±14 versus −542±46 picoamperes per picofarad [pA/pF]; −140 mV; P −[84+542] pA/pF; 1 μg each; −140 mV). Confocal microscopy analysis showed that the fluorescent protein-tagged S369X subunits were predominantly retained in the ER when expressed alone; however, the expression of S369X subunits to the plasma membrane was partially restored when coexpressed with WT. Fluorescence resonance energy transfer analysis demonstrated direct protein-protein interactions between WT and S369X subunits in the intracellular compartment. Conclusions— The S369X mutation causes a loss of the ER export motif. However, the trafficking deficiency can be partially rescued by directly assembling with the WT protein, resulting in a limited restoration of plasma membrane localization and channel function. This alleviation may explain why our patient presented with a relatively mild ATS phenotype. |
| Databáze: | OpenAIRE |
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