The E646D-ATP13A4 Mutation Associated with Autism Reveals a Defect in Calcium Regulation |
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Authors: | Janaki Vallipuram Jeffrey Grenville " target="_blank">Dorota A Crawford |
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Institution: | (1) Department of Biology, York University, Toronto, ON, Canada;(2) School of Kinesiology and Health Science, York University, Toronto, ON, Canada;(3) Neuroscience Graduate Diploma Program, York University, Toronto, ON, Canada;(4) Faculty of Health, York University, 4700 Keele Street, Bethune College, Rm. 346, Toronto, ON, M3J-1P3, Canada; |
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Abstract: | ATP13A4 is a member of the subfamily of P5-type ATPases. P5-type ATPases are the least studied of the P-type ATPase subfamilies with no ion specificities assigned to them. In order
to elucidate ATP13A4 function, we studied the protein’s subcellular localization and tested whether it is involved in calcium
regulation. The intracellular calcium concentration was measured in COS-7 cells over-expressing mouse ATP13A4 using ratiometric
calcium imaging with fura-2 AM as a calcium indicator. The results of this study show that ATP13A4 is localized to the endoplasmic
reticulum (ER). Furthermore, we demonstrate that over-expression of ATP13A4 in COS-7 cells caused a significant increase in
the intracellular calcium level. Interestingly, over-expression of the sequence variant containing a substitution of aspartic
acid for a glutamic acid (E646D), previously found in patients with autism spectrum disorder (ASD), did not increase the free
cellular calcium likely due to the mutation. In this study, we also describe the expression of ATP13A4 during mouse embryonic development. Quantitative real-time PCR revealed that ATP13A4 was highly expressed at embryonic days 15–17, when neurogenesis takes place. The present study is the first to provide further
insights into the biological role of a P5-type ATPase. Our results demonstrate that ATP13A4 may be involved in calcium regulation and that its expression is developmentally
regulated. Overall, this study provides support for the hypothesis that ATP13A4 may play a vital role in the developing nervous
system and its impairment can contribute to the symptoms seen in ASD. |
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