ELOVL5 mutations cause spinocerebellar ataxia 38.
The American Journal of Human Genetics. 2014-08-01; 95(2): 209-217
DOI: 10.1016/j.ajhg.2014.07.001
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1. Am J Hum Genet. 2014 Aug 7;95(2):209-17. doi: 10.1016/j.ajhg.2014.07.001. Epub
2014 Jul 24.
ELOVL5 mutations cause spinocerebellar ataxia 38.
Di Gregorio E(1), Borroni B(2), Giorgio E(3), Lacerenza D(3), Ferrero M(3), Lo
Buono N(3), Ragusa N(3), Mancini C(3), Gaussen M(4), Calcia A(3), Mitro N(5),
Hoxha E(6), Mura I(7), Coviello DA(7), Moon YA(8), Tesson C(4), Vaula G(9),
Couarch P(10), Orsi L(9), Duregon E(11), Papotti MG(11), Deleuze JF(12), Imbert
J(13), Costanzi C(2), Padovani A(2), Giunti P(14), Maillet-Vioud M(15), Durr
A(16), Brice A(16), Tempia F(6), Funaro A(3), Boccone L(17), Caruso D(6),
Stevanin G(18), Brusco A(19).
Author information:
(1)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.
(2)Department of Neurology, University of Brescia, 25100 Brescia, Italy.
(3)Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
(4)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.
(5)Department of Pharmacological and Biomolecular Sciences, University of Milano,
20133 Milano, Italy.
(6)Neuroscience Institute Cavalieri Ottolenghi, University of Torino, 10043
Orbassano, Italy.
(7)Laboratory of Human Genetics, Galliera Hospital, 16128 Genova, Italy.
(8)Department of Molecular Genetics, University of Texas Southwestern Medical
Center, Dallas, TX 75390-9046, USA.
(9)Neurologic Division 1, Department of Neuroscience and Mental Health, Azienda
Ospedaliera Universitaria Città della Salute e della Scienza, 10126 Torino,
Italy.
(10)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.
(11)Department of Oncology, University of Torino at San Luigi Hospital, 10043
Orbassano, Italy.
(12)Centre National de Génotypage, 91057 Evry, France.
(13)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.
(14)Department of Molecular Neuroscience, University College London Institute of
Neurology, WC1 N3BG London, UK.
(15)Centre Hospitalier General de Montlucon, 03113 Montluçon, France.
(16)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.
(17)Ospedale Regionale Microcitemie, Azienda Unità Sanitaria Locale 8, 09121
Cagliari, Italy.
(18)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.
(19)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: .
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.
Copyright © 2014 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2014.07.001
PMCID: PMC4129408
PMID: 25065913 [Indexed for MEDLINE]