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ELOVL5 mutations cause spinocerebellar ataxia 38
- Publication Year :
- 2014
-
Abstract
- Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases.
- Subjects :
- Male
Docosahexaenoic Acids
Genotype
Fatty Acid Elongases
Genetic Linkage
Golgi Apparatus
Biology
medicine.disease_cause
Endoplasmic Reticulum
Mice
Purkinje Cells
Genetic linkage
Acetyltransferases
Cerebellum
Report
medicine
Genetics
Missense mutation
Animals
Humans
Spinocerebellar Ataxias
Genetics(clinical)
Amino Acid Sequence
Gene
Genetics (clinical)
Aged
Aged, 80 and over
Mutation
Arachidonic Acid
Endoplasmic reticulum
Haplotype
Middle Aged
Subcellular localization
medicine.disease
Lipid Metabolism
Pedigree
Haplotypes
Italy
Spinocerebellar ataxia
Female
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....1c79db7785603f97963c324ab0be41a7