title: Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1.
abstract: BACKGROUND
  Dystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association.
  
  
  METHODS
  We used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and immunolabelling on cultured fibroblasts to demonstrate the lower expression and the mislocalization of the protein.
  
  
  RESULTS
  We report on a boy born from consanguineous healthy parents, who presented at three years of age with rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy. We identified regions of homozygosity and performed whole exome sequencing that revealed a homozygous missense mutation in TOR1AIP1. The mutation, absent in controls, results in a change of a highly conserved glutamic acid to alanine. TOR1AIP1 encodes lamina-associated polypeptide 1 (LAP1), a transmembrane protein ubiquitously expressed in the inner nuclear membrane. LAP1 interacts with torsinA, the protein mutated in DYT1-dystonia. In vitro studies in fibroblasts of the patient revealed reduced expression of LAP1 and its mislocalization and aggregation in the endoplasmic reticulum as underlying pathogenic mechanisms.
  
  
  CONCLUSIONS
  The pathogenic role of TOR1AIP1 mutation is supported by a) the involvement of a highly conserved amino acid, b) the absence of the mutation in controls, c) the functional interaction of LAP1 with torsinA, and d) mislocalization of LAP1 in patient cells. Of note, cardiomyopathy has been reported in LAP1-null mice and in patients with the TOR1AIP1 nonsense mutation. Other cases will help delineate the clinical spectrum of LAP1-related mutations.
authors.affiliation: Inserm U1141, Université Paris Diderot-Sorbonne Paris Cité, DHU PROTECT, Paris, F-75019, France. imen.dorboz@inserm.fr.
authors.forename: Imen
authors.initials: I
authors.lastname: Dorboz
authors.affiliation: Inserm, U1127, Paris, F-75013, France. marie.coutelier@icm-institute.org.|CNRS, UMR 7225, Paris, 75013, France. marie.coutelier@icm-institute.org.|Université Pierre et Marie Curie - Paris 6, UMR_S 1127, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 75013, Paris, France. marie.coutelier@icm-institute.org.|Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 75013, Paris, France. marie.coutelier@icm-institute.org.|Laboratoire de Génétique Humaine, Institut de Duve, UCL, 1200, Bruxelles, Belgium. marie.coutelier@icm-institute.org.
authors.forename: Marie
authors.initials: M
authors.lastname: Coutelier
authors.affiliation: Inserm, U974, Paris, F-75013, France. a.bertrand@institut-myologie.org.|Université Pierre et Marie Curie - Paris 6, UM 76; CNRS, UMR 7215; Institut de Myologie, Paris, F-75013, France. a.bertrand@institut-myologie.org.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Bertrand
authors.affiliation: Service de génétique, CHU du Sart Tilman, Liège, Belgium. jh.caberg@chu.ulg.ac.be.
authors.forename: Jean-Hubert
authors.initials: JH
authors.lastname: Caberg
authors.affiliation: Service d'Imagerie Pédiatrique, Hôpital Robert Debré, 75019, Paris, France. monique.elmaleh@rdb.aphp.fr.
authors.forename: Monique
authors.initials: M
authors.lastname: Elmaleh-Bergès
authors.affiliation: Inserm, U974, Paris, F-75013, France. J.laine@institut-myologie.org.|Université Pierre et Marie Curie - Paris 6, UM 76; CNRS, UMR 7215; Institut de Myologie, Paris, F-75013, France. J.laine@institut-myologie.org.|Département de Physiologie, Université Pierre et Marie Curie - Paris 6, Site Pitié-Salpêtrière, Paris, F-75013, France. J.laine@institut-myologie.org.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Lainé
authors.affiliation: Inserm, U1127, Paris, F-75013, France. giovanni.stevanin@upmc.fr.|CNRS, UMR 7225, Paris, 75013, France. giovanni.stevanin@upmc.fr.|Université Pierre et Marie Curie - Paris 6, UMR_S 1127, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 75013, Paris, France. giovanni.stevanin@upmc.fr.|Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 75013, Paris, France. giovanni.stevanin@upmc.fr.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: Inserm, U974, Paris, F-75013, France. g.bonne@institut-myologie.org.|Université Pierre et Marie Curie - Paris 6, UM 76; CNRS, UMR 7215; Institut de Myologie, Paris, F-75013, France. g.bonne@institut-myologie.org.|AP-HP, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, F-75013, France. g.bonne@institut-myologie.org.
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.affiliation: Inserm U1141, Université Paris Diderot-Sorbonne Paris Cité, DHU PROTECT, Paris, F-75019, France. odile.boespflug@rdb.aphp.fr.|Service de neurologie pédiatrique et des maladies métaboliques, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris, 75019, Paris, France. odile.boespflug@rdb.aphp.fr.
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.affiliation: Service de neurologie pédiatrique et des maladies métaboliques, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris, 75019, Paris, France. l.servais@institut-myologie.org.|Centre de Référence des Maladies Neuromusculaires, Hôpital de La Citadelle, 4000, Liège, Belgium. l.servais@institut-myologie.org.|Institut de Myologie, Bâtiment Babinski, Hôpital de La Pitié Salpêtrière, 48/83 boulevard de l'Hôpital, 75013, Paris, France. l.servais@institut-myologie.org.
authors.forename: Laurent
authors.initials: L
authors.lastname: Servais
mesh_terms: D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics*; D018929:Cell Culture Techniques; D002526:Cerebellar Diseases / Q000209:etiology / Q000235:genetics*; D002675:Child, Preschool; D004421:Dystonia / Q000209:etiology / Q000235:genetics*; D059472:Exome; D005347:Fibroblasts / Q000378:metabolism*; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D018832:Molecular Chaperones; C108175:TOR1A protein, human