Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1

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• 作者：Imen Dorboz (1)
  Marie Coutelier (2) (3) (4) (5) (6)
  Anne T Bertrand (7) (8)
  Jean-Hubert Caberg (9)
  Monique Elmaleh-Berg猫s (10)
  Jeanne Lain茅 (11) (7) (8)
  Giovanni Stevanin (2) (3) (4) (5)
  Gis猫le Bonne (12) (7) (8)
  Odile Boespflug-Tanguy (1) (13)
  Laurent Servais (13) (14) (15)
  
  1. Inserm U1141 ; Universit茅 Paris Diderot-Sorbonne Paris Cit茅 ; DHU PROTECT ; Paris ; F-75019 ; France
  2. Inserm ; U1127 ; Paris ; F-75013 ; France
  3. CNRS ; UMR 7225 ; Paris ; 75013 ; France
  4. Universit茅 Pierre et Marie Curie - Paris 6 ; UMR_S 1127 ; Institut du Cerveau et de la Moelle 茅pini猫re ; CHU Piti茅-Salp锚tri猫re ; 75013 ; Paris ; France
  5. Laboratoire de Neurog茅n茅tique ; Ecole Pratique des Hautes Etudes ; Institut du Cerveau et de la Moelle 茅pini猫re ; CHU Piti茅-Salp锚tri猫re ; 75013 ; Paris ; France
  6. Laboratoire de G茅n茅tique Humaine ; Institut de Duve ; UCL ; 1200 ; Bruxelles ; Belgium
  7. Inserm ; U974 ; Paris ; F-75013 ; France
  8. Universit茅 Pierre et Marie Curie - Paris 6 ; UM 76 ; CNRS ; UMR 7215 ; Institut de Myologie ; Paris ; F-75013 ; France
  9. Service de g茅n茅tique ; CHU du Sart Tilman ; Li猫ge ; Belgium
  10. Service d鈥橧magerie P茅diatrique ; H么pital Robert Debr茅 ; 75019 ; Paris ; France
  11. D茅partement de Physiologie ; Universit茅 Pierre et Marie Curie - Paris 6 ; Site Piti茅-Salp锚tri猫re ; Paris ; F-75013 ; France
  12. AP-HP ; Groupe Hospitalier Piti茅-Salp锚tri猫re ; U.F. Cardiog茅n茅tique et Myog茅n茅tique ; Service de Biochimie M茅tabolique ; Paris ; F-75013 ; France
  13. Service de neurologie p茅diatrique et des maladies m茅taboliques ; H么pital Robert Debr茅 ; Assistance Publique des H么pitaux de Paris ; 75019 ; Paris ; France
  14. Centre de R茅f茅rence des Maladies Neuromusculaires ; H么pital de La Citadelle ; 4000 ; Li猫ge ; Belgium
  15. Institut de Myologie ; B芒timent Babinski ; H么pital de La Piti茅 Salp锚tri猫re ; 48/83 boulevard de l鈥橦么pital ; 75013 ; Paris ; France
  
• 关键词：Dystonia ; Cerebellar atrophy ; Torsin ; Nuclear membrane
• 刊名：Orphanet Journal of Rare Diseases
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：9
• 期：1
• 全文大小：1,439 KB
• 参考文献：1. Boukhris, A, Schule, R, Loureiro, JL, Louren莽o, CM, Mundwiller, E, Gonzalez, MA, Charles, P, Gauthier, J, Rekik, I, Acosta Lebrigio, RF, Gaussen, M, Speziani, F, Ferbert, A, Feki, I, Caballero-Oteyza, A, Dionne-Laporte, A, Amri, M, Noreau, A, Forlani, S, Cruz, VT, Mochel, F, Coutinho, P, Dion, P, Mhiri, C, Schols, L, Pouget, J, Darios, F, Rouleau, GA, Marques, W, Brice, A (2013) Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet 93: pp. 118-123 CrossRef
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  3. Cattin, ME, Bertrand, AT, Schlossarek, S, Bihan, MC, Skov Jensen, S, Neuber, C, Crocini, C, Maron, S, Lain茅, J, Mougenot, N, Varnous, S, Fromes, Y, Hansen, A, Eschenhagen, T, Decostre, V, Carrier, L, Bonne, G (2013) Heterozygous LmnadelK32 mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity. Hum Mol Genet 22: pp. 3152-3164 CrossRef
  4. Kim, CE1, Perez, A, Perkins, G, Ellisman, MH, Dauer, WT (2010) A molecular mechanism underlying the neural-specific defect in torsinA mutant mice. Proc Natl Acad Sci U S A 107: pp. 9861-9866 CrossRef
  5. De Carvalho Aguiar, PM, Ozelius, LJ (2002) Classification and genetics of dystonia. Lancet Neurol 1: pp. 316-325 CrossRef
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  8. Hamilton, EM, Polder, E, Vanderver, A, Naidu, S, Schiffmann, R, Fisher, K, Ragu啪, AB, Blumkin, L, Berkel, CG, Waisfisz, Q, Simons, C, Taft, RJ, Abbink, TE, Wolf, NI, Knaap, MS (2014) Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation. Brain 137: pp. 1921-1930 CrossRef
  9. Le Ber, I, Clot, F, Vercueil, L, Camuzat, A, Vi茅mont, M, Benamar, N, Li猫ge, P, Ouvrard-Hernandez, AM, Pollak, P, Stevanin, G, Brice, A, D眉rr, A (2006) Predominant dystonia with marked cerebellar atrophy: a rare phenotype in familial dystonia. Neurology 67: pp. 1769-1773 CrossRef
  10. Borgelt, LM, Franson, KL, Nussbaum, AM, Wang, GS (2013) The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 33: pp. 195-209 CrossRef
  11. Koppel, BS, Brust, JC, Fife, T, Bronstein, J, Youssof, S, Gronseth, G, Gloss, D (2014) Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 82: pp. 1556-1563 CrossRef
  12. Zhao, C, Brown, RS, Chase, AR, Eisele, MR, Schlieker, C (2013) Regulation of Torsin ATPases by LAP1 and LULL1. Proc Natl Acad Sci U S A 110: pp. 1545-1554 CrossRef
  13. Jungwirth, M, Dear, ML, Brown, P, Holbrook, K, Goodchild, R (2010) Relative tissue expression of homologous torsinB correlates with the neuronal specific importance of DYT1 dystonia-associated torsinA. Hum Mol Genet 19: pp. 888-900 CrossRef
  14. Shin, JY, M茅ndez-L贸pez, I, Wang, Y, Hays, AP, Tanji, K, Lefkowitch, JH, Schulze, PC, Worman, HJ, Dauer, WT (2013) Lamina-associated polypeptide-1 interacts with the muscular dystrophy protein emerin and is essential for skeletal muscle maintenance. Dev Cell 26: pp. 591-603 devcel.2013.08.012" target="_blank" title="It opens in new window">CrossRef
  15. Kayman-Kurekci, G, Talim, B, Korkusuz, P, Sayar, N, Sarioglu, T, Oncel, I, Sharafi, P, Gundesli, H, Balci-Hayta, B, Purali, N, Serdaroglu-Oflazer, P, Topaloglu, H, Dincer, P (2014) Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies. Neuromuscul Disord 24: pp. 624-633 CrossRef
  
• 刊物主题：Medicine/Public Health, general; Pharmacology/Toxicology; Medicinal Chemistry;
• 出版者：BioMed Central
• ISSN：1750-1172

文摘

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 and relevance 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.