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Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy
Matthew R Sapio1, Annick Salzmann, Monique Vessaz
1Department of Neuroscience, Albert Einstein College of Medicine,Bronx, New York 10461,USA.
The Journal of Biological Chemistry
|October 30, 2012
Summary
Mutations in Carboxypeptidase A6 (CPA6) are linked to epilepsy. This study identified new CPA6 mutations that reduce enzyme activity and protein levels, further supporting its role in human epilepsy.
Area of Science:
- Neurogenetics
- Enzymology
- Molecular Biology
Background:
- Carboxypeptidase A6 (CPA6), a metallocarboxypeptidase, is expressed in the brain during development.
- Previous studies linked human CPA6 mutations to febrile seizures and temporal lobe epilepsy.
Purpose of the Study:
- To screen for additional CPA6 mutations in patients with febrile seizures and focal epilepsy.
- To investigate the functional impact of identified CPA6 mutations on enzyme activity and protein stability.
Main Methods:
- Screening of CPA6 mutations in epilepsy patients and public databases.
- Analysis of modeled proCPA6 protein structure and mutated amino acid function.
- In vitro testing of mutant CPA6 protein expression and activity in HEK293 cells.
Main Results:
- Several CPA6 mutations were found to reduce enzyme activity or extracellular protein levels.
- Mutations affecting extracellular CPA6 levels did not significantly impact protein folding.
- Three mutations reducing extracellular CPA6 levels were identified in epilepsy patients.
Conclusions:
- CPA6 mutations are further implicated in the pathogenesis of human epilepsy.
- Identified rare mutations inactivate CPA6, potentially contributing to epileptic phenotypes.
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