TorsinA-interacting protein 2 (TOR1AIP2) variants in an autosomal dominant combined dystonia-hemichorea-hemiballismus syndrome in two families
Kafantari, Efthymia LU ; Hernandez, Victoria J. ; Necpál, Jan ; Leonidou, Marina ; Baureder, Regina LU ; Jech, Robert ; Zech, Michael ; Schwartz, Thomas U. and Puschmann, Andreas LU
(2024)
In Parkinsonism and Related Disorders
122.
p.6-6
- Abstract
- Background: Combined movement disorders often represent a diagnostic challenge. Dystonia is a movement disorder characterized by genetic and clinical heterogeneity. A recurring p.(Glu303del)-deletion in TOR1A is a well-established cause for DYT-TOR1A (DYT1) dystonia. TOR1A encodes TorsinA, an AAA+ ATPase located in the nuclear envelope. Hemichorea-hemiballismus syndrome can occur after basal ganglia lesions or in a small subset of patients with non-ketotic hyperglycemia.
Methods: Two families with a with a novel hereditary hemiballism-hemichorea-dystonia phenotype were followed clinically. Surface electromyograms were obtained from several affected muscles of the most severely affected individual. Whole exome data from >1,000... (More) - Background: Combined movement disorders often represent a diagnostic challenge. Dystonia is a movement disorder characterized by genetic and clinical heterogeneity. A recurring p.(Glu303del)-deletion in TOR1A is a well-established cause for DYT-TOR1A (DYT1) dystonia. TOR1A encodes TorsinA, an AAA+ ATPase located in the nuclear envelope. Hemichorea-hemiballismus syndrome can occur after basal ganglia lesions or in a small subset of patients with non-ketotic hyperglycemia.
Methods: Two families with a with a novel hereditary hemiballism-hemichorea-dystonia phenotype were followed clinically. Surface electromyograms were obtained from several affected muscles of the most severely affected individual. Whole exome data from >1,000 dystonia patients searched for variants in the gene nominated. Functional analysis via a co-purification assay was performed.
Results: We identified a TOR1AIP2 NM_001199260.1 c.1234A>G p.(Arg412Gly) variant which is very rare in databases and was absent from >1,000 dystonia patients. TOR1AIP2 encodes LULL1, a transmembrane protein that activates TorsinA, and correct interaction between TorsinA and LULL1 is essential for proper nuclear envelope architecture. The p.(Arg412Gly) variant disrupts the binding interface between TorsinA and LULL1 around p.Arg412; this same interface is also impaired in DYT1. Co-purification assay revealed that interaction between TorsinA-LULL1Arg412Gly is weaker than the wild-type interaction, and that it resembles the situation in DYT1 (TorsinAΔE303-LULL1). In a second family, the very rare variant TOR1AIP2 p.(Gln338His) co-segregated with milder dystonia, hemichorea, and stereotyped leg flexion during gait. The clinical phenotype of both families shared proximal arm movements as seen in of DYT1, and flutter in facial musculature. As in DYT1, expressivity of movement disorder symptoms was variable in both families. Electromyography showed 400-700msec bursts in relevant muscles during the hemiballistic movements.
Conclusions: Several proteins in the nuclear envelope have been implicated in various forms of neurodevelopmental disorders with dystonia. Our findings suggest TOR1AIP2 as a new gene possibly implicated in a particular syndrome of dystonia with hemiballism and/or hemichorea.
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Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/ef5be9eb-6536-4e8c-882a-c2b883c09787
- author
- Kafantari, Efthymia
LU
; Hernandez, Victoria J.
; Necpál, Jan
; Leonidou, Marina
; Baureder, Regina
LU
; Jech, Robert
; Zech, Michael
; Schwartz, Thomas U.
and Puschmann, Andreas
LU
- organization
- publishing date
- 2024-05-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Parkinsonism and Related Disorders
- volume
- 122
- article number
- 106574
- pages
- 6 - 6
- publisher
- Elsevier
- ISSN
- 1873-5126
- DOI
- 10.1016/j.parkreldis.2024.106574
- language
- English
- LU publication?
- yes
- id
- ef5be9eb-6536-4e8c-882a-c2b883c09787
- date added to LUP
- 2024-10-01 16:06:53
- date last changed
- 2024-10-02 14:08:03
@misc{ef5be9eb-6536-4e8c-882a-c2b883c09787,
abstract = {{Background: Combined movement disorders often represent a diagnostic challenge. Dystonia is a movement disorder characterized by genetic and clinical heterogeneity. A recurring p.(Glu303del)-deletion in TOR1A is a well-established cause for DYT-TOR1A (DYT1) dystonia. TOR1A encodes TorsinA, an AAA+ ATPase located in the nuclear envelope. Hemichorea-hemiballismus syndrome can occur after basal ganglia lesions or in a small subset of patients with non-ketotic hyperglycemia.<br/><br/>Methods: Two families with a with a novel hereditary hemiballism-hemichorea-dystonia phenotype were followed clinically. Surface electromyograms were obtained from several affected muscles of the most severely affected individual. Whole exome data from >1,000 dystonia patients searched for variants in the gene nominated. Functional analysis via a co-purification assay was performed.<br/><br/>Results: We identified a TOR1AIP2 NM_001199260.1 c.1234A>G p.(Arg412Gly) variant which is very rare in databases and was absent from >1,000 dystonia patients. TOR1AIP2 encodes LULL1, a transmembrane protein that activates TorsinA, and correct interaction between TorsinA and LULL1 is essential for proper nuclear envelope architecture. The p.(Arg412Gly) variant disrupts the binding interface between TorsinA and LULL1 around p.Arg412; this same interface is also impaired in DYT1. Co-purification assay revealed that interaction between TorsinA-LULL1Arg412Gly is weaker than the wild-type interaction, and that it resembles the situation in DYT1 (TorsinAΔE303-LULL1). In a second family, the very rare variant TOR1AIP2 p.(Gln338His) co-segregated with milder dystonia, hemichorea, and stereotyped leg flexion during gait. The clinical phenotype of both families shared proximal arm movements as seen in of DYT1, and flutter in facial musculature. As in DYT1, expressivity of movement disorder symptoms was variable in both families. Electromyography showed 400-700msec bursts in relevant muscles during the hemiballistic movements.<br/><br/>Conclusions: Several proteins in the nuclear envelope have been implicated in various forms of neurodevelopmental disorders with dystonia. Our findings suggest TOR1AIP2 as a new gene possibly implicated in a particular syndrome of dystonia with hemiballism and/or hemichorea.<br/>}},
author = {{Kafantari, Efthymia and Hernandez, Victoria J. and Necpál, Jan and Leonidou, Marina and Baureder, Regina and Jech, Robert and Zech, Michael and Schwartz, Thomas U. and Puschmann, Andreas}},
issn = {{1873-5126}},
language = {{eng}},
month = {{05}},
note = {{Conference Abstract}},
pages = {{6--6}},
publisher = {{Elsevier}},
series = {{Parkinsonism and Related Disorders}},
title = {{TorsinA-interacting protein 2 (TOR1AIP2) variants in an autosomal dominant combined dystonia-hemichorea-hemiballismus syndrome in two families}},
url = {{http://dx.doi.org/10.1016/j.parkreldis.2024.106574}},
doi = {{10.1016/j.parkreldis.2024.106574}},
volume = {{122}},
year = {{2024}},
}