KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking.
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Gallego-Iradi C, Bickford JS, Khare S, Hall A, Nick JA, Salmasinia D, Wawrowsky K, Bannykh S, Huynh DP, Rincon-Limas DE, Pulst SM, Nick HS, Fernandez-Funez P, Waters MF
KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking.
Neurobiol Dis. 2014 Nov;71:270-9. doi: 10.1016/j.nbd.2014.08.020. Epub 2014 Aug 22.
- PubMed ID
- 25152487 [ View in PubMed]
- Abstract
Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant disease resulting from mutations in KCNC3 (Kv3.3), a voltage-gated potassium channel. The KCNC3(R420H) mutation was first identified as causative for SCA13 in a four-generation Filipino kindred with over 20 affected individuals. Electrophysiological analyses in oocytes previously showed that this mutation did not lead to a functional channel and displayed a dominant negative phenotype. In an effort to identify the molecular basis of this allelic form of SCA13, we first determined that human KCNC3(WT) and KCNC3(R420H) display disparate post-translational modifications, and the mutant protein has reduced complex glycan adducts. Immunohistochemical analyses demonstrated that KCNC3(R420H) was not properly trafficking to the plasma membrane and surface biotinylation demonstrated that KCNC3(R420H) exhibited only 24% as much surface expression as KCNC3(WT). KCNC3(R420H) trafficked through the ER but was retained in the Golgi. KCNC3(R420H) expression results in altered Golgi and cellular morphology. Electron microscopy of KCNC3(R420H) localization further supports retention in the Golgi. These results are specific to the KCNC3(R420H) allele and provide new insight into the molecular basis of disease manifestation in SCA13.