title: TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment.
abstract: Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.
authors: 1 Centre National de la Recherche Scientifique, UMR8199, Institut de Biologie, F-59000, Lille, France 2 Institut National de la Santé et de la Recherche Médicale, INSERM U837, and Université de Lille Nord de France, F-59045, Lille, France.
authors: Jérôme
authors: J
authors: Delplanque
authors: 3 Département de Neurologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: David
authors: D
authors: Devos
authors: 2 Institut National de la Santé et de la Recherche Médicale, INSERM U837, and Université de Lille Nord de France, F-59045, Lille, France 4 Pôle de Biochimie et Biologie moléculaire, Centre de Biologie-Pathologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Vincent
authors: V
authors: Huin
authors: 4 Pôle de Biochimie et Biologie moléculaire, Centre de Biologie-Pathologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Alexandre
authors: A
authors: Genet
authors: 1 Centre National de la Recherche Scientifique, UMR8199, Institut de Biologie, F-59000, Lille, France.
authors: Olivier
authors: O
authors: Sand
authors: 3 Département de Neurologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Caroline
authors: C
authors: Moreau
authors: 5 Laboratoire des maladies rares : Génétique et métabolisme (MRGM/EA4576), Université Bordeaux Segalen, F-33076, Bordeaux, France.
authors: Cyril
authors: C
authors: Goizet
authors: 6 Département de Neurologie, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, F-75651, Paris, France.
authors: Perrine
authors: P
authors: Charles
authors: 7 Institut de Génétique et de Biologie moléculaire et cellulaire (IGBMC), INSERMU964/CNRS-UMR7104/ Strasbourg, F-67404, Illkirch-Graffenstaden, France.
authors: Mathieu
authors: M
authors: Anheim
authors: 8 Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, F-75013, Paris, France.
authors: Marie Lorraine
authors: ML
authors: Monin
authors: 2 Institut National de la Santé et de la Recherche Médicale, INSERM U837, and Université de Lille Nord de France, F-59045, Lille, France.
authors: Luc
authors: L
authors: Buée
authors: 3 Département de Neurologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Alain
authors: A
authors: Destée
authors: 3 Département de Neurologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Guillaume
authors: G
authors: Grolez
authors: 9 Département de Neuroradiologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Christine
authors: C
authors: Delmaire
authors: 3 Département de Neurologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Kathy
authors: K
authors: Dujardin
authors: 10 Département de Neuropédiatrie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Delphine
authors: D
authors: Dellacherie
authors: 11 Fédération de Génétique, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, F-75013, Paris, France 12 Institut du cerveau et de la moelle épinière, INSERM U1127/CNRS UMR7225, Université de Paris VI, F-75013, Paris, France.
authors: Alexis
authors: A
authors: Brice
authors: 11 Fédération de Génétique, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, F-75013, Paris, France 13 Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Hésam Université, F-75013 Paris, France.
authors: Giovanni
authors: G
authors: Stevanin
authors: 4 Pôle de Biochimie et Biologie moléculaire, Centre de Biologie-Pathologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France.
authors: Isabelle
authors: I
authors: Strubi-Vuillaume
authors: 11 Fédération de Génétique, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, F-75013, Paris, France 12 Institut du cerveau et de la moelle épinière, INSERM U1127/CNRS UMR7225, Université de Paris VI, F-75013, Paris, France.
authors: Alexandra
authors: A
authors: Dürr
authors: 2 Institut National de la Santé et de la Recherche Médicale, INSERM U837, and Université de Lille Nord de France, F-59045, Lille, France 4 Pôle de Biochimie et Biologie moléculaire, Centre de Biologie-Pathologie, Centre Hospitalier Régional et Universitaire de Lille, F-59037, Lille, France bernard.sablonniere@inserm.fr.
authors: Bernard
authors: B
authors: Sablonnière
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics* / Q000523:psychology; D015331:Cohort Studies; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D005602:France; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000523:psychology; D007361:Intelligence Tests; D007438:Introns; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D009483:Neuropsychological Tests; D010375:Pedigree; D016133:Polymerase Chain Reaction; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C000592813:TMEM240 protein, human
keywords: TMEM240; exome; spinocerebellar ataxia