A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620173
Title:
A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.
Authors:
Ahmed, M. Y.; Al-Khayat, A.; Al-Murshedi, F.; Al-Futaisi, A.; Chioza, B.A.; Pedro Fernandez-Murray, J.; Self, J. E.; Salter, C. G.; Harlalka, G. V.; Rawlins, Lettie E; Al-Zuhaibi, S.; Al-Azri, F.; Al-Rashdi, F.; Cazenave-Gassiot, A.; Wenk, M. R.; Al-Salmi, F.; Patton, M. A.; Silver, D. L.; Baple, E. L.; McMaster, C. R.; Crosby, Andrew H.
Abstract:
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.
Citation:
A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis. 2017 Mar 1;140(3):547-554 Brain
Publisher:
Oxford Journals
Journal:
Brain : a journal of neurology
Issue Date:
3-Jan-2017
URI:
http://hdl.handle.net/11287/620173
DOI:
10.1093/brain/aww318
PubMed ID:
28052917
Additional Links:
https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/aww318
Note:
This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
1460-2156
Appears in Collections:
Honorary contracts publications; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorAhmed, M. Y.en
dc.contributor.authorAl-Khayat, A.en
dc.contributor.authorAl-Murshedi, F.en
dc.contributor.authorAl-Futaisi, A.en
dc.contributor.authorChioza, B.A.en
dc.contributor.authorPedro Fernandez-Murray, J.en
dc.contributor.authorSelf, J. E.en
dc.contributor.authorSalter, C. G.en
dc.contributor.authorHarlalka, G. V.en
dc.contributor.authorRawlins, Lettie Een
dc.contributor.authorAl-Zuhaibi, S.en
dc.contributor.authorAl-Azri, F.en
dc.contributor.authorAl-Rashdi, F.en
dc.contributor.authorCazenave-Gassiot, A.en
dc.contributor.authorWenk, M. R.en
dc.contributor.authorAl-Salmi, F.en
dc.contributor.authorPatton, M. A.en
dc.contributor.authorSilver, D. L.en
dc.contributor.authorBaple, E. L.en
dc.contributor.authorMcMaster, C. R.en
dc.contributor.authorCrosby, Andrew H.en
dc.date.accessioned2017-01-17T10:12:35Z-
dc.date.available2017-01-17T10:12:35Z-
dc.date.issued2017-01-03-
dc.identifier.citationA mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis. 2017 Mar 1;140(3):547-554 Brainen
dc.identifier.issn1460-2156-
dc.identifier.pmid28052917-
dc.identifier.doi10.1093/brain/aww318-
dc.identifier.urihttp://hdl.handle.net/11287/620173-
dc.description.abstractMutations 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.en
dc.language.isoenen
dc.publisherOxford Journalsen
dc.relation.urlhttps://academic.oup.com/brain/article-lookup/doi/10.1093/brain/aww318en
dc.rightsArchived with thanks to Brain : a journal of neurologyen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleA mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.en
dc.typeJournal Articleen
dc.identifier.journalBrain : a journal of neurologyen
dc.description.noteThis article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionIn press (epub ahead of print)en

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