ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis
The FA Elongase-4 (ELOVL4) enzyme mediates biosynthesis of both very long chain (VLC)-PUFAs and VLC-saturated FA (VLC-SFAs). VLC-PUFAs play critical roles in retina and sperm function, whereas VLC-SFAs are predominantly associated with brain function and maintenance of the skin permeability barrier....
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S002222752200150X |
| _version_ | 1797944082938462208 |
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| author | Yeboah Kofi Gyening Neeraj Kumar Chauhan Madison Tytanic Vicki Ea Richard S. Brush Martin-Paul Agbaga |
| author_facet | Yeboah Kofi Gyening Neeraj Kumar Chauhan Madison Tytanic Vicki Ea Richard S. Brush Martin-Paul Agbaga |
| author_sort | Yeboah Kofi Gyening |
| collection | DOAJ |
| description | The FA Elongase-4 (ELOVL4) enzyme mediates biosynthesis of both very long chain (VLC)-PUFAs and VLC-saturated FA (VLC-SFAs). VLC-PUFAs play critical roles in retina and sperm function, whereas VLC-SFAs are predominantly associated with brain function and maintenance of the skin permeability barrier. While some ELOVL4 mutations cause Autosomal Dominant Stargardt-like Macular Dystrophy (STGD3), other ELOVL4 point mutations, such as L168F and W246G, affect the brain and/or skin, leading to Spinocerebellar Ataxia-34 (SCA34) and Erythrokeratodermia variabilis. The mechanisms by which these ELOVL4 mutations alter VLC-PUFA and VLC-SFA biosynthesis to cause the different tissue-specific pathologies are not well understood. To understand how these mutations alter VLC-PUFA and VLC-SFA biosynthesis, we expressed WT-ELOVL4, L168F, and W246G ELOVL4 variants in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. Total lipids were extracted, converted to FA methyl esters, and quantified by gas chromatography. We showed that L168F and W246G mutants were capable of VLC-PUFA biosynthesis. W246G synthesized and accumulated 32:6n3, while L168F exhibited gain of function in VLC-PUFA biosynthesis as it made 38:5n3, which we did not detect in WT-ELOVL4 or W246G-expressing cells. However, compared with WT-ELOVL4, both L168F and W246G mutants were deficient in VLC-SFA biosynthesis, especially the W246G protein, which showed negligible VLC-SFA biosynthesis. These results suggest VLC-PUFA biosynthetic capabilities of L168F and W246G in the retina, which may explain the lack of retinal phenotype in SCA34. Defects in VLC-SFA biosynthesis by these variants may be a contributing factor to the pathogenic mechanism of SCA34 and Erythrokeratodermia variabilis. |
| first_indexed | 2024-04-10T20:34:01Z |
| format | Article |
| id | doaj.art-837b278313024f33a618f388b91f0798 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-04-10T20:34:01Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-837b278313024f33a618f388b91f07982023-01-25T04:14:41ZengElsevierJournal of Lipid Research0022-22752023-01-01641100317ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid BiosynthesisYeboah Kofi Gyening0Neeraj Kumar Chauhan1Madison Tytanic2Vicki Ea3Richard S. Brush4Martin-Paul Agbaga5Departments of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Ophthalmology, Dean McGee Eye Institute, Oklahoma City, Oklahoma, USADepartments of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Ophthalmology, Dean McGee Eye Institute, Oklahoma City, Oklahoma, USADepartments of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Ophthalmology, Dean McGee Eye Institute, Oklahoma City, Oklahoma, USADepartment of Ophthalmology, Dean McGee Eye Institute, Oklahoma City, Oklahoma, USADepartment of Ophthalmology, Dean McGee Eye Institute, Oklahoma City, Oklahoma, USA; Departments of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USADepartments of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Ophthalmology, Dean McGee Eye Institute, Oklahoma City, Oklahoma, USA; Departments of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; For correspondence: Martin-Paul AgbagaThe FA Elongase-4 (ELOVL4) enzyme mediates biosynthesis of both very long chain (VLC)-PUFAs and VLC-saturated FA (VLC-SFAs). VLC-PUFAs play critical roles in retina and sperm function, whereas VLC-SFAs are predominantly associated with brain function and maintenance of the skin permeability barrier. While some ELOVL4 mutations cause Autosomal Dominant Stargardt-like Macular Dystrophy (STGD3), other ELOVL4 point mutations, such as L168F and W246G, affect the brain and/or skin, leading to Spinocerebellar Ataxia-34 (SCA34) and Erythrokeratodermia variabilis. The mechanisms by which these ELOVL4 mutations alter VLC-PUFA and VLC-SFA biosynthesis to cause the different tissue-specific pathologies are not well understood. To understand how these mutations alter VLC-PUFA and VLC-SFA biosynthesis, we expressed WT-ELOVL4, L168F, and W246G ELOVL4 variants in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. Total lipids were extracted, converted to FA methyl esters, and quantified by gas chromatography. We showed that L168F and W246G mutants were capable of VLC-PUFA biosynthesis. W246G synthesized and accumulated 32:6n3, while L168F exhibited gain of function in VLC-PUFA biosynthesis as it made 38:5n3, which we did not detect in WT-ELOVL4 or W246G-expressing cells. However, compared with WT-ELOVL4, both L168F and W246G mutants were deficient in VLC-SFA biosynthesis, especially the W246G protein, which showed negligible VLC-SFA biosynthesis. These results suggest VLC-PUFA biosynthetic capabilities of L168F and W246G in the retina, which may explain the lack of retinal phenotype in SCA34. Defects in VLC-SFA biosynthesis by these variants may be a contributing factor to the pathogenic mechanism of SCA34 and Erythrokeratodermia variabilis.http://www.sciencedirect.com/science/article/pii/S002222752200150Xlipidselongation of very long chain fatty acid-4eye/retinasaturated fatty acidfatty acid metabolismomega-3 fatty acids |
| spellingShingle | Yeboah Kofi Gyening Neeraj Kumar Chauhan Madison Tytanic Vicki Ea Richard S. Brush Martin-Paul Agbaga ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis Journal of Lipid Research lipids elongation of very long chain fatty acid-4 eye/retina saturated fatty acid fatty acid metabolism omega-3 fatty acids |
| title | ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis |
| title_full | ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis |
| title_fullStr | ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis |
| title_full_unstemmed | ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis |
| title_short | ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis |
| title_sort | elovl4 mutations that cause spinocerebellar ataxia 34 differentially alter very long chain fatty acid biosynthesis |
| topic | lipids elongation of very long chain fatty acid-4 eye/retina saturated fatty acid fatty acid metabolism omega-3 fatty acids |
| url | http://www.sciencedirect.com/science/article/pii/S002222752200150X |
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