Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family
Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense va...
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Genetics |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fgene.2018.00085/full |
| _version_ | 1828378021335138304 |
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| author | Hena Ahmad Hena Ahmad Teresa Requena Lidia Frejo Marien Cobo Alvaro Gallego-Martinez Francisco Martin Jose A. Lopez-Escamez Jose A. Lopez-Escamez Adolfo M. Bronstein Adolfo M. Bronstein |
| author_facet | Hena Ahmad Hena Ahmad Teresa Requena Lidia Frejo Marien Cobo Alvaro Gallego-Martinez Francisco Martin Jose A. Lopez-Escamez Jose A. Lopez-Escamez Adolfo M. Bronstein Adolfo M. Bronstein |
| author_sort | Hena Ahmad |
| collection | DOAJ |
| description | Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense variant in the ELF2 gene at chr4:g.140058846 C > T, c.10G > A, p.A4T which segregated in all affected patients. By using transduced BE (2)-M17 cells, we found that the mutated ELF2 (mt-ELF2) gene increased ATXN2 and reduced ELOVL5 gene expression, the causal genes of type 2 and type 38 spinocerebellar ataxias. Both, western blot and confocal microscopy confirmed an increase of ataxin-2 in BE(2)-M17 cells transduced with lentivirus expressing mt-ELF2 (CEE-mt-ELF2), which was not observed in cells transduced with lentivirus expressing wt-ELF2 (CEE-wt-ELF2). Moreover, we observed a significant decrease in the number and size of lipid droplets in the CEE-mt-ELF2-transduced BE (2)-M17 cells, but not in the CEE-wt-ELF2-transduced BE (2)-M17. Furthermore, changes in the expression of ELOVL5 could be related with the reduction of lipid droplets in BE (2)-M17 cells. This work supports that ELF2 gene regulates the expression of ATXN2 and ELOVL5 genes, and defines new molecular links in the pathophysiology of cerebellar ataxias. |
| first_indexed | 2024-04-14T08:20:31Z |
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| language | English |
| last_indexed | 2024-04-14T08:20:31Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj.art-f29fa71288bc4c22b88d43437e6cf2622022-12-22T02:04:14ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-03-01910.3389/fgene.2018.00085330919Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS FamilyHena Ahmad0Hena Ahmad1Teresa Requena2Lidia Frejo3Marien Cobo4Alvaro Gallego-Martinez5Francisco Martin6Jose A. Lopez-Escamez7Jose A. Lopez-Escamez8Adolfo M. Bronstein9Adolfo M. Bronstein10Division of Brain Sciences, Imperial College, Charing Cross Hospital, London, United KingdomNational Hospital for Neurology & Neurosurgery, London, United KingdomOtology and Neurotology Group CTS495, Department of Genomic Medicine, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, SpainOtology and Neurotology Group CTS495, Department of Genomic Medicine, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, SpainGene and Cell Therapy Group, Department of Genomic Medicine, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, SpainOtology and Neurotology Group CTS495, Department of Genomic Medicine, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, SpainGene and Cell Therapy Group, Department of Genomic Medicine, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, SpainOtology and Neurotology Group CTS495, Department of Genomic Medicine, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, SpainDepartment of Otolaryngology, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospital Virgen de las Nieves, Universidad de Granada, Granada, SpainDivision of Brain Sciences, Imperial College, Charing Cross Hospital, London, United KingdomNational Hospital for Neurology & Neurosurgery, London, United KingdomCerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense variant in the ELF2 gene at chr4:g.140058846 C > T, c.10G > A, p.A4T which segregated in all affected patients. By using transduced BE (2)-M17 cells, we found that the mutated ELF2 (mt-ELF2) gene increased ATXN2 and reduced ELOVL5 gene expression, the causal genes of type 2 and type 38 spinocerebellar ataxias. Both, western blot and confocal microscopy confirmed an increase of ataxin-2 in BE(2)-M17 cells transduced with lentivirus expressing mt-ELF2 (CEE-mt-ELF2), which was not observed in cells transduced with lentivirus expressing wt-ELF2 (CEE-wt-ELF2). Moreover, we observed a significant decrease in the number and size of lipid droplets in the CEE-mt-ELF2-transduced BE (2)-M17 cells, but not in the CEE-wt-ELF2-transduced BE (2)-M17. Furthermore, changes in the expression of ELOVL5 could be related with the reduction of lipid droplets in BE (2)-M17 cells. This work supports that ELF2 gene regulates the expression of ATXN2 and ELOVL5 genes, and defines new molecular links in the pathophysiology of cerebellar ataxias.http://journal.frontiersin.org/article/10.3389/fgene.2018.00085/fullcerebellar ataxiavestibular hypofunctionneuropathywhole-exome sequencingETS domain |
| spellingShingle | Hena Ahmad Hena Ahmad Teresa Requena Lidia Frejo Marien Cobo Alvaro Gallego-Martinez Francisco Martin Jose A. Lopez-Escamez Jose A. Lopez-Escamez Adolfo M. Bronstein Adolfo M. Bronstein Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family Frontiers in Genetics cerebellar ataxia vestibular hypofunction neuropathy whole-exome sequencing ETS domain |
| title | Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family |
| title_full | Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family |
| title_fullStr | Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family |
| title_full_unstemmed | Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family |
| title_short | Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family |
| title_sort | clinical and functional characterization of a missense elf2 variant in a canvas family |
| topic | cerebellar ataxia vestibular hypofunction neuropathy whole-exome sequencing ETS domain |
| url | http://journal.frontiersin.org/article/10.3389/fgene.2018.00085/full |
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