title: ELOVL5 mutations cause spinocerebellar ataxia 38.
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.
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy; Medical Genetics Unit, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino, Italy.
authors: Eleonora
authors: E
authors: Di Gregorio
authors: Department of Neurology, University of Brescia, 25100 Brescia, Italy.
authors: Barbara
authors: B
authors: Borroni
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Elisa
authors: E
authors: Giorgio
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Daniela
authors: D
authors: Lacerenza
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Marta
authors: M
authors: Ferrero
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Nicola
authors: N
authors: Lo Buono
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Neftj
authors: N
authors: Ragusa
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Cecilia
authors: C
authors: Mancini
authors: Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Neurogenetics team, École Pratique des Hautes Études, HéSam Université, 75013 Paris, France.
authors: Marion
authors: M
authors: Gaussen
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Alessandro
authors: A
authors: Calcia
authors: Department of Pharmacological and Biomolecular Sciences, University of Milano, 20133 Milano, Italy.
authors: Nico
authors: N
authors: Mitro
authors: Neuroscience Institute Cavalieri Ottolenghi, University of Torino, 10043 Orbassano, Italy.
authors: Eriola
authors: E
authors: Hoxha
authors: Laboratory of Human Genetics, Galliera Hospital, 16128 Genova, Italy.
authors: Isabella
authors: I
authors: Mura
authors: Laboratory of Human Genetics, Galliera Hospital, 16128 Genova, Italy.
authors: Domenico A
authors: DA
authors: Coviello
authors: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
authors: Young-Ah
authors: YA
authors: Moon
authors: Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Neurogenetics team, École Pratique des Hautes Études, HéSam Université, 75013 Paris, France.
authors: Christelle
authors: C
authors: Tesson
authors: Neurologic Division 1, Department of Neuroscience and Mental Health, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino, Italy.
authors: Giovanna
authors: G
authors: Vaula
authors: Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.
authors: Philippe
authors: P
authors: Couarch
authors: Neurologic Division 1, Department of Neuroscience and Mental Health, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino, Italy.
authors: Laura
authors: L
authors: Orsi
authors: Department of Oncology, University of Torino at San Luigi Hospital, 10043 Orbassano, Italy.
authors: Eleonora
authors: E
authors: Duregon
authors: Department of Oncology, University of Torino at San Luigi Hospital, 10043 Orbassano, Italy.
authors: Mauro Giulio
authors: MG
authors: Papotti
authors: Centre National de Génotypage, 91057 Evry, France.
authors: Jean-François
authors: JF
authors: Deleuze
authors: Transcriptomic and Genomic Marseille-Luminy platform, Technological Advances for Genomics and Clinics Laboratory, Institut National de la Santé et de la Recherche Médicale UMR_S 1090, Aix-Marseille University, 13009 Marseille, France.
authors: Jean
authors: J
authors: Imbert
authors: Department of Neurology, University of Brescia, 25100 Brescia, Italy.
authors: Chiara
authors: C
authors: Costanzi
authors: Department of Neurology, University of Brescia, 25100 Brescia, Italy.
authors: Alessandro
authors: A
authors: Padovani
authors: Department of Molecular Neuroscience, University College London Institute of Neurology, WC1 N3BG London, UK.
authors: Paola
authors: P
authors: Giunti
authors: Centre Hospitalier General de Montlucon, 03113 Montluçon, France.
authors: Marcel
authors: M
authors: Maillet-Vioud
authors: Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Fédération de Génétique, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
authors: Alexandra
authors: A
authors: Durr
authors: Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Fédération de Génétique, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
authors: Alexis
authors: A
authors: Brice
authors: Neuroscience Institute Cavalieri Ottolenghi, University of Torino, 10043 Orbassano, Italy.
authors: Filippo
authors: F
authors: Tempia
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Ada
authors: A
authors: Funaro
authors: Ospedale Regionale Microcitemie, Azienda Unità Sanitaria Locale 8, 09121 Cagliari, Italy.
authors: Loredana
authors: L
authors: Boccone
authors: Neuroscience Institute Cavalieri Ottolenghi, University of Torino, 10043 Orbassano, Italy.
authors: Donatella
authors: D
authors: Caruso
authors: Institut National de la Santé et de la Recherche Médicale U1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (Paris 6) UMR_S 1127, Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Neurogenetics team, École Pratique des Hautes Études, HéSam Université, 75013 Paris, France; Fédération de Génétique, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
authors: Giovanni
authors: G
authors: Stevanin
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy; Medical Genetics Unit, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino, Italy. Electronic address: alfredo.brusco@unito.it.
authors: Alfredo
authors: A
authors: Brusco
mesh_terms: D000123:Acetyltransferases / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood; D002531:Cerebellum / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000097:blood; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000081031:Fatty Acid Elongases; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006056:Golgi Apparatus / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007558:Italy; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011689:Purkinje Cells / Q000166:cytology; D020754:Spinocerebellar Ataxias / Q000235:genetics*
chemical_list: C000630954:ELOVL5 protein, human; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases