摘要
Background: CACNA1A encodes Cav2.1, the pore- forming subunit of P/Q- type voltage- gated calcium channel complexes. Mutations in CACNA1A cause a wide ran ge of neurologic disturbances variably associated with cerebellar degeneration. Functional studies to date focus on electrophysiologic defects that do not adequ ately explain the phenotypic findings. Objective: To investigate whether some mi ssense mutations might interfere with protein folding and trafficking, eventuall y leading to protein aggregation and neuronal injury. Methods: The authors studi ed the functional consequences of two pore missense mutations, C287Y and G293R, in two families with EA2, one newly discovered and the other previously reported . Both mutations caused episodic and interictal ataxia. The biophysical properti es of mutant and wild type calcium channels were examined by whole- cell patch - clamp recordings in transfected COS- 7 cells. The plasma membrane targeting was visualized by confocal fluorescence imaging on Cav2.1 tagged with green fluo rescent protein. Results: The mutant channels exhibited a marked reduction in cu rrent expression and deficiencies in plasma membrane targeting. Conclusions: In addition to altered channel function, the deficiency in protein misfolding and t rafficking associated with the C287Y and G293R mutants may contribute to the slo wly progressive cerebellar ataxia.
Background: CACNA1A encodes Cav2.1, the pore- forming subunit of P/Q- type voltage- gated calcium channel complexes. Mutations in CACNA1A cause a wide ran ge of neurologic disturbances variably associated with cerebellar degeneration. Functional studies to date focus on electrophysiologic defects that do not adequ ately explain the phenotypic findings. Objective: To investigate whether some mi ssense mutations might interfere with protein folding and trafficking, eventuall y leading to protein aggregation and neuronal injury. Methods: The authors studi ed the functional consequences of two pore missense mutations, C287Y and G293R, in two families with EA2, one newly discovered and the other previously reported . Both mutations caused episodic and interictal ataxia. The biophysical properti es of mutant and wild type calcium channels were examined by whole- cell patch - clamp recordings in transfected COS- 7 cells. The plasma membrane targeting was visualized by confocal fluorescence imaging on Cav2.1 tagged with green fluo rescent protein. Results: The mutant channels exhibited a marked reduction in cu rrent expression and deficiencies in plasma membrane targeting. Conclusions: In addition to altered channel function, the deficiency in protein misfolding and t rafficking associated with the C287Y and G293R mutants may contribute to the slo wly progressive cerebellar ataxia.
出处
《世界核心医学期刊文摘（神经病学分册）》
2005年第10期53-54,共2页
Digest of the World Core Medical Journals:Clinical Neurology
