ELOVL5 Mutations Cause Spinocerebellar Ataxia 38
Eleonora Di Gregorio
(1, 2)
,
Barbara Borroni
(3)
,
Elisa Giorgio
(2)
,
Daniela Lacerenza
(2)
,
Marta Ferrero
(2)
,
Nicola Lo Buono
(2)
,
Neftj Ragusa
(2)
,
Cecilia Mancini
(2)
,
Marion Gaussen
(4, 5)
,
Alessandro Calcia
(2)
,
Nico Mitro
(6)
,
Eriola Hoxha
(2)
,
Isabella Mura
(7)
,
Domenico A. Coviello
(7)
,
Young-Ah Moon
(8)
,
Christelle Tesson
(5, 4)
,
Giovanna Vaula
(1)
,
Philippe Couarch
(5)
,
Laura Orsi
(1)
,
Eleonora Duregon
(2)
,
Mauro Giulio Papotti
(2)
,
Jean-François Deleuze
(9)
,
Jean Imbert
(10)
,
Chiara Costanzi
(3)
,
Alessandro Padovani
(3)
,
Paola Giunti
(11)
,
Marcel Maillet-Vioud
(12)
,
Alexandra Durr
(5, 13)
,
Alexis Brice
(5, 13)
,
Filippo Tempia
(14)
,
Ada Funaro
(2)
,
Loredana Boccone
(15)
,
Donatella Caruso
(14)
,
Giovanni Stevanin
(5, 4, 13)
,
Alfredo Brusco
(2, 1)
1
Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino
2 UNITO - Università degli studi di Torino = University of Turin
3 UniBs - Università degli Studi di Brescia = University of Brescia
4 EPHE - École Pratique des Hautes Études
5 ICM - Institut du Cerveau = Paris Brain Institute
6 UNIMI - Università degli Studi di Milano = University of Milan
7 Galliera Hospital
8 University of Texas Southwestern Medical Center
9 CNG - Centre National de Génotypage
10 TAGC - Theories and Approaches of Genomic Complexity
11 Institute of Neurology [London]
12 Centre hospitalier Montluçon -Néris les bains
13 CHU Pitié-Salpêtrière [AP-HP]
14 NICO - Neuroscience Institute Cavalieri Ottolenghi [Turin]
15 AUSL della Romagna - Azienda Unità Sanitaria Locale della Romagna
2 UNITO - Università degli studi di Torino = University of Turin
3 UniBs - Università degli Studi di Brescia = University of Brescia
4 EPHE - École Pratique des Hautes Études
5 ICM - Institut du Cerveau = Paris Brain Institute
6 UNIMI - Università degli Studi di Milano = University of Milan
7 Galliera Hospital
8 University of Texas Southwestern Medical Center
9 CNG - Centre National de Génotypage
10 TAGC - Theories and Approaches of Genomic Complexity
11 Institute of Neurology [London]
12 Centre hospitalier Montluçon -Néris les bains
13 CHU Pitié-Salpêtrière [AP-HP]
14 NICO - Neuroscience Institute Cavalieri Ottolenghi [Turin]
15 AUSL della Romagna - Azienda Unità Sanitaria Locale della Romagna
Alexandra Durr
- Fonction : Auteur
- PersonId : 758970
- ORCID : 0000-0002-8921-7104
- IdRef : 148675018
Giovanni Stevanin
- Fonction : Auteur
- PersonId : 758031
- ORCID : 0000-0001-9368-8657
- IdRef : 119149982
Alfredo Brusco
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- Fonction : Auteur correspondant
- PersonId : 895021
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Résumé
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.