Impaired lipid metabolism mechanism
This is the first description of HSP linked to a mutation in the SELENOI gene (also known as EPT1). The complicated form of HSP, inherited autosomally recessively, associated with this gene mutation is as yet unclassified.
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.
SOURCE: Brain. 2017 Jan 3. pii: aww318. doi: 10.1093/brain/aww318. [Epub ahead of print] PMID: 28052917 [PubMed – as supplied by publisher] © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.
A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.
Ahmed MY1, Al-Khayat A2, Al-Murshedi F3, Al-Futaisi A4, Chioza BA1, Pedro Fernandez-Murray J5, Self JE6, Salter CG7, Harlalka GV1, Rawlins LE1, Al-Zuhaibi S8, Al-Azri F9, Al-Rashdi F10, Cazenave-Gassiot A11,12, Wenk MR11,12, Al-Salmi F2, Patton MA1,2, Silver DL13, Baple EL14, McMaster CR5, Crosby AH14.
1 Medical Research (Level 4), University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK.
2 Department of Biology, College of Science, Sultan Qaboos University, Sultanate of Oman.
3 Department of Genetics, College of Medicine, Sultan Qaboos University, Sultanate of Oman.
4 Department of Paediatrics, Sultan Qaboos University Hospital, Sultanate of Oman.
5 Department of Pharmacology, Dalhousie University, Halifax, NS, B3H 4H7, Canada.
6 Faculty of Medicine, University of Southampton, UK.
7 West Midlands Regional Genetics Service, Birmingham Women’s NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2TG, UK.
8 Department of Ophthalmology, Sultan Qaboos University Hospital, Sultanate of Oman.
9 Department of Radiology and Molecular Imaging, Sultan Qaboos University Hospital, Sultanate of Oman.
10 Department of Paediatrics, Sameal Hospital, Ministry of Health, Sultanate of Oman.
11 SLING, Life Sciences Institute, National University of Singapore, Singapore.
12 Department of Biochemistry, National University of Singapore, Singapore.
13 Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore.
14 Medical Research (Level 4), University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK [email protected] [email protected].