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Mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis

Mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis
Mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis
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.
0006-8950
1-8
Ahmed, Mustafa Y.
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Al-Khayat, Aisha
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Al-Murshedi, Fathiya
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Al-Futaisi, Amna
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Choiza, Barry A.
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Fernandez-Murray, Pedro
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Self, Jay E.
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Salter, Claire G.
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Harlalka, Gaurav V.
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Rawlins, Lettie E.
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Al-Zuhaibi, Sana
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Al-Azri, Faisal
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Al-Rashdi, Fatma
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Cazenave Gassiot, Amaury
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Wenk, Marcus R.
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Al-Salmi, Fatema
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Patton, Michael A.
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Silver, David L.
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Baple, Emma L.
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McMaster, Christopher R.
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Crosby, Andrew H.
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Ahmed, Mustafa Y.
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Al-Khayat, Aisha
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Al-Murshedi, Fathiya
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Al-Futaisi, Amna
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Choiza, Barry A.
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Fernandez-Murray, Pedro
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Self, Jay E.
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Salter, Claire G.
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Harlalka, Gaurav V.
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Rawlins, Lettie E.
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Al-Zuhaibi, Sana
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Al-Azri, Faisal
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Al-Rashdi, Fatma
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Cazenave Gassiot, Amaury
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Wenk, Marcus R.
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Al-Salmi, Fatema
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Patton, Michael A.
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Silver, David L.
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Baple, Emma L.
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McMaster, Christopher R.
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Crosby, Andrew H.
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Ahmed, Mustafa Y., Al-Khayat, Aisha, Al-Murshedi, Fathiya, Al-Futaisi, Amna, Choiza, Barry A., Fernandez-Murray, Pedro, Self, Jay E., Salter, Claire G., Harlalka, Gaurav V., Rawlins, Lettie E., Al-Zuhaibi, Sana, Al-Azri, Faisal, Al-Rashdi, Fatma, Cazenave Gassiot, Amaury, Wenk, Marcus R., Al-Salmi, Fatema, Patton, Michael A., Silver, David L., Baple, Emma L., McMaster, Christopher R. and Crosby, Andrew H. (2017) Mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis Brain, pp. 1-8.

Record type: Article

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.

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Accepted/In Press date: 19 October 2016
e-pub ahead of print date: 4 January 2017
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 403005
URI: http://eprints.soton.ac.uk/id/eprint/403005
ISSN: 0006-8950
PURE UUID: b3e5e6ee-4d13-4e15-ae58-ff7d9368b353
ORCID for Jay E. Self: ORCID iD orcid.org/0000-0002-1030-9963

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Date deposited: 02 Feb 2017 15:56
Last modified: 03 Nov 2017 05:25

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Contributors

Author: Mustafa Y. Ahmed
Author: Aisha Al-Khayat
Author: Fathiya Al-Murshedi
Author: Amna Al-Futaisi
Author: Barry A. Choiza
Author: Pedro Fernandez-Murray
Author: Jay E. Self ORCID iD
Author: Claire G. Salter
Author: Gaurav V. Harlalka
Author: Lettie E. Rawlins
Author: Sana Al-Zuhaibi
Author: Faisal Al-Azri
Author: Fatma Al-Rashdi
Author: Amaury Cazenave Gassiot
Author: Marcus R. Wenk
Author: Fatema Al-Salmi
Author: Michael A. Patton
Author: David L. Silver
Author: Emma L. Baple
Author: Christopher R. McMaster
Author: Andrew H. Crosby

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