A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis
Pedro Fernandez-Murray, J
Oxford University Press (OUP)
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
Mutations in genes involved in lipid metabolism have increasingly been associated with various subtypes of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative motor neuron disorders characterized by spastic paraparesis. Here, we report an unusual autosomal recessive neurodegenerative condition, best classified as a complicated form of hereditary spastic paraplegia, associated with mutation in the ethanolaminephosphotransferase 1 (EPT1) gene (now known as SELENOI), responsible for the final step in Kennedy pathway forming phosphatidylethanolamine from CDP-ethanolamine. Phosphatidylethanolamine is a glycerophospholipid that, together with phosphatidylcholine, constitutes more than half of the total phospholipids in eukaryotic cell membranes. We determined that the mutation defined dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis. Additionally, due to central nervous system inaccessibility we undertook quantification of phosphatidylethanolamine levels and species in patient and control blood samples as an indication of liver phosphatidylethanolamine biosynthesis. Although this revealed alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients, overall phosphatidylethanolamine levels were broadly unaffected indicating that in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways. These studies define the first human disorder arising due to defective CDP-ethanolamine biosynthesis and provide new insight into the role of Kennedy pathway components in human neurological function.
The study was supported by the Medical Research Council (G1002279, to A.H.C) (G1001931 to E.L.B), Newlife Foundation for Disabled Children, The Research CouncilOman Grant # ORG-SQU-HSS-09-016, the National University of Singapore via the Life Sciences Institute (LSI, to M.R.W.), the National Research Foundation (NRFI2015- 05, to M.R.W.), the Agency for Science, Technology and Research (A*Star) via a BMRC-SERC joint grant (BMRCSERC 112 148 0006, to M.R.W.), the Singapore Ministry of Health’s National Medical Research Council (CBRG/069/ 2014,to D.L.S.), and the Singapore Ministry of Education’s (Tier2 grant MOE2014-T2-2-018, to D.L.S.).
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