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Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia.

Mencacci, NE; Brockmann, MM; Dai, J; Pajusalu, S; Atasu, B; Campos, J; Pino, G; Gonzalez-Latapi, P; Patzke, C; Schwake, M; et al. Mencacci, NE; Brockmann, MM; Dai, J; Pajusalu, S; Atasu, B; Campos, J; Pino, G; Gonzalez-Latapi, P; Patzke, C; Schwake, M; Tucci, A; Pittman, A; Simon-Sanchez, J; Carvill, GL; Balint, B; Wiethoff, S; Warner, TT; Papandreou, A; Soo, A; Rein, R; Kadastik-Eerme, L; Puusepp, S; Reinson, K; Tomberg, T; Hanagasi, H; Gasser, T; Bhatia, KP; Kurian, MA; Lohmann, E; Õunap, K; Rosenmund, C; Südhof, TC; Wood, NW; Krainc, D; Acuna, C (2021) Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia. J Clin Invest, 131 (7). e140625. ISSN 1558-8238 https://doi.org/10.1172/JCI140625
SGUL Authors: Pittman, Alan Michael

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Abstract

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

Item Type: Article
Additional Information: © 2021, American Society for Clinical Investigation.
Keywords: Genetic diseases, Genetics, Movement disorders, Neuroscience, Synapses, Genetic diseases, Genetics, Movement disorders, Neuroscience, Synapses, Immunology, 11 Medical and Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: J Clin Invest
ISSN: 1558-8238
Language: eng
Dates:
DateEvent
1 April 2021Published
4 February 2021Published Online
3 February 2021Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
MR/S006753/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
R37 NS096241NINDS NIH HHSUNSPECIFIED
RP-2016-07-019Department of Healthhttp://dx.doi.org/10.13039/501100000276
DFG1158-S02NUNSPECIFIEDUNSPECIFIED
PUT355Estonian Research Councilhttp://dx.doi.org/10.13039/501100002301
PRG471Estonian Research Councilhttp://dx.doi.org/10.13039/501100002301
PUTJD827Estonian Research Councilhttp://dx.doi.org/10.13039/501100002301
57451854/62180003DAAD/ANIDUNSPECIFIED
PubMed ID: 33539324
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112922
Publisher's version: https://doi.org/10.1172/JCI140625

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