Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1
Orphanet J Rare Dis. 2014-11-26; 9(1):
DOI: 10.1186/S13023-014-0174-9
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1. Orphanet J Rare Dis. 2014 Nov 26;9:174. doi: 10.1186/s13023-014-0174-9.
Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a
missense mutation in TOR1AIP1.
Dorboz I(1), Coutelier M(2)(3)(4)(5)(6), Bertrand AT(7)(8), Caberg JH(9),
Elmaleh-Bergès M(10), Lainé J(11)(12)(13), Stevanin G(14)(15)(16)(17), Bonne
G(18)(19)(20), Boespflug-Tanguy O(21)(22), Servais L(23)(24)(25).
Author information:
(1)Inserm U1141, Université Paris Diderot-Sorbonne Paris Cité, DHU PROTECT,
Paris, F-75019, France. .
(2)Inserm, U1127, Paris, F-75013, France. .
(3)CNRS, UMR 7225, Paris, 75013, France. .
(4)Université Pierre et Marie Curie – Paris 6, UMR_S 1127, Institut du Cerveau et
de la Moelle épinière, CHU Pitié-Salpêtrière, 75013, Paris, France.
.
(5)Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du
Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 75013, Paris, France.
.
(6)Laboratoire de Génétique Humaine, Institut de Duve, UCL, 1200, Bruxelles,
Belgium. .
(7)Inserm, U974, Paris, F-75013, France. .
(8)Université Pierre et Marie Curie – Paris 6, UM 76; CNRS, UMR 7215; Institut de
Myologie, Paris, F-75013, France. .
(9)Service de génétique, CHU du Sart Tilman, Liège, Belgium.
.
(10)Service d’Imagerie Pédiatrique, Hôpital Robert Debré, 75019, Paris, France.
.
(11)Inserm, U974, Paris, F-75013, France. .
(12)Université Pierre et Marie Curie – Paris 6, UM 76; CNRS, UMR 7215; Institut
de Myologie, Paris, F-75013, France. .
(13)Département de Physiologie, Université Pierre et Marie Curie – Paris 6, Site
Pitié-Salpêtrière, Paris, F-75013, France. .
(14)Inserm, U1127, Paris, F-75013, France. .
(15)CNRS, UMR 7225, Paris, 75013, France. .
(16)Université Pierre et Marie Curie – Paris 6, UMR_S 1127, Institut du Cerveau
et de la Moelle épinière, CHU Pitié-Salpêtrière, 75013, Paris, France.
.
(17)Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du
Cerveau et de la Moelle épinière, CHU Pitié-Salpêtrière, 75013, Paris, France.
.
(18)Inserm, U974, Paris, F-75013, France. .
(19)Université Pierre et Marie Curie – Paris 6, UM 76; CNRS, UMR 7215; Institut
de Myologie, Paris, F-75013, France. .
(20)AP-HP, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et
Myogénétique, Service de Biochimie Métabolique, Paris, F-75013, France.
.
(21)Inserm U1141, Université Paris Diderot-Sorbonne Paris Cité, DHU PROTECT,
Paris, F-75019, France. .
(22)Service de neurologie pédiatrique et des maladies métaboliques, Hôpital
Robert Debré, Assistance Publique des Hôpitaux de Paris, 75019, Paris, France.
.
(23)Service de neurologie pédiatrique et des maladies métaboliques, Hôpital
Robert Debré, Assistance Publique des Hôpitaux de Paris, 75019, Paris, France.
.
(24)Centre de Référence des Maladies Neuromusculaires, Hôpital de La Citadelle,
4000, Liège, Belgium. .
(25)Institut de Myologie, Bâtiment Babinski, Hôpital de La Pitié Salpêtrière,
48/83 boulevard de l’Hôpital, 75013, Paris, France.
.
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.
DOI: 10.1186/s13023-014-0174-9
PMCID: PMC4302636
PMID: 25425325 [Indexed for MEDLINE]