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

Mustafa Y. Ahmed, Aisha Al-Khayat, Fathiya Al-Murshedi, Amna Al-Futaisi, Barry A. Chioza, J. Pedro Fernandez-Murray, Jay E. Self, Claire G. Salter, Gaurav V. Harlalka, Lettie E. Rawlins, Sana Al-Zuhaibi, Faisal Al-Azri, Fatma Al-Rashdi, Amaury Cazenave-Gassiot, Markus R. Wenk, Fatema Al-Salmi, Michael A. Patton, David L. Silver, Emma L. Baple, Christopher R. McMaster & 1 others Andrew H. Crosby

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)547-554
Number of pages8
JournalBrain : a journal of neurology
Volume140
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

Fingerprint

Ethanolaminephosphotransferase
Phospholipids
Mutation
Hereditary Spastic Paraplegia
Spastic Paraparesis
Glycerophospholipids
Motor Neurons
Eukaryotic Cells
phosphatidylethanolamine
Pathway
Phosphatidylcholines
Lipid Metabolism
Genes
Central Nervous System
Cell Membrane
Blood
Gene

Keywords

  • EPT1 mutation
  • hereditary spastic paraplegia
  • Kennedy pathway
  • phospholipid biosynthesis
  • whole exome sequencing

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis. / Ahmed, Mustafa Y.; Al-Khayat, Aisha; Al-Murshedi, Fathiya; Al-Futaisi, Amna; Chioza, Barry A.; Pedro Fernandez-Murray, J.; 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, Markus R.; Al-Salmi, Fatema; Patton, Michael A.; Silver, David L.; Baple, Emma L.; McMaster, Christopher R.; Crosby, Andrew H.

In: Brain : a journal of neurology, Vol. 140, No. 3, 01.03.2017, p. 547-554.

Research output: Contribution to journalArticle

Ahmed, MY, Al-Khayat, A, Al-Murshedi, F, Al-Futaisi, A, Chioza, BA, Pedro Fernandez-Murray, J, Self, JE, Salter, CG, Harlalka, GV, Rawlins, LE, Al-Zuhaibi, S, Al-Azri, F, Al-Rashdi, F, Cazenave-Gassiot, A, Wenk, MR, Al-Salmi, F, Patton, MA, Silver, DL, Baple, EL, McMaster, CR & Crosby, AH 2017, 'A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis', Brain : a journal of neurology, vol. 140, no. 3, pp. 547-554. https://doi.org/10.1093/brain/aww318
Ahmed, Mustafa Y. ; Al-Khayat, Aisha ; Al-Murshedi, Fathiya ; Al-Futaisi, Amna ; Chioza, Barry A. ; Pedro Fernandez-Murray, J. ; 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, Markus R. ; Al-Salmi, Fatema ; Patton, Michael A. ; Silver, David L. ; Baple, Emma L. ; McMaster, Christopher R. ; Crosby, Andrew H. / A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis. In: Brain : a journal of neurology. 2017 ; Vol. 140, No. 3. pp. 547-554.
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AU - Pedro Fernandez-Murray, J.

AU - Self, Jay E.

AU - Salter, Claire G.

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AU - Al-Azri, Faisal

AU - Al-Rashdi, Fatma

AU - Cazenave-Gassiot, Amaury

AU - Wenk, Markus R.

AU - Al-Salmi, Fatema

AU - Patton, Michael A.

AU - Silver, David L.

AU - Baple, Emma L.

AU - McMaster, Christopher R.

AU - Crosby, Andrew H.

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