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

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Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia. / Mencacci, Niccolò E.; Brockmann, Marisa M.; Dai, Jinye; Pajusalu, Sander; Atasu, Burcu; Campos, Joaquin; Pino, Gabriela; Gonzalez-Latapi, Paulina; Patzke, Christopher; Schwake, Michael; Tucci, Arianna; Pittman, Alan; Simon-Sanchez, Javier; Carvill, Gemma L.; Balint, Bettina; Wiethoff, Sarah; Warner, Thomas T.; Papandreou, Apostolos; Soo, Audrey; Rein, Reet; Kadastik-Eerme, Liis; Puusepp, Sanna; Reinson, Karit; Tomberg, Tiiu; Hanagasi, Hasmet; Gasser, Thomas; Bhatia, Kailash P.; Kurian, Manju A.; Lohmann, Ebba; Õunap, Katrin; Rosenmund, Christian; Südhof, Thomas C.; Wood, Nicholas W.; Krainc, Dimitri; Acuna, Claudio.

In: J CLIN INVEST, Vol. 131, No. 7, e140625, 01.04.2021.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, vol. 131, no. 7, e140625. https://doi.org/10.1172/JCI140625

APA

Mencacci, N. E., Brockmann, M. M., 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, G. L., Balint, B., Wiethoff, S., Warner, T. T., Papandreou, A., Soo, A., ... Acuna, C. (2021). Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia. J CLIN INVEST, 131(7), [e140625]. https://doi.org/10.1172/JCI140625

Vancouver

Mencacci NE, Brockmann MM, Dai J, Pajusalu S, Atasu B, Campos J et al. Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia. J CLIN INVEST. 2021 Apr 1;131(7). e140625. https://doi.org/10.1172/JCI140625

Bibtex

@article{205bcd04d29944b4b59315b01b6f8957,
title = "Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia",
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.",
author = "Mencacci, {Niccol{\`o} E.} and Brockmann, {Marisa M.} and Jinye Dai and Sander Pajusalu and Burcu Atasu and Joaquin Campos and Gabriela Pino and Paulina Gonzalez-Latapi and Christopher Patzke and Michael Schwake and Arianna Tucci and Alan Pittman and Javier Simon-Sanchez and Carvill, {Gemma L.} and Bettina Balint and Sarah Wiethoff and Warner, {Thomas T.} and Apostolos Papandreou and Audrey Soo and Reet Rein and Liis Kadastik-Eerme and Sanna Puusepp and Karit Reinson and Tiiu Tomberg and Hasmet Hanagasi and Thomas Gasser and Bhatia, {Kailash P.} and Kurian, {Manju A.} and Ebba Lohmann and Katrin {\~O}unap and Christian Rosenmund and S{\"u}dhof, {Thomas C.} and Wood, {Nicholas W.} and Dimitri Krainc and Claudio Acuna",
year = "2021",
month = apr,
day = "1",
doi = "10.1172/JCI140625",
language = "English",
volume = "131",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "7",

}

RIS

TY - JOUR

T1 - Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia

AU - Mencacci, Niccolò E.

AU - Brockmann, Marisa M.

AU - Dai, Jinye

AU - Pajusalu, Sander

AU - Atasu, Burcu

AU - Campos, Joaquin

AU - Pino, Gabriela

AU - Gonzalez-Latapi, Paulina

AU - Patzke, Christopher

AU - Schwake, Michael

AU - Tucci, Arianna

AU - Pittman, Alan

AU - Simon-Sanchez, Javier

AU - Carvill, Gemma L.

AU - Balint, Bettina

AU - Wiethoff, Sarah

AU - Warner, Thomas T.

AU - Papandreou, Apostolos

AU - Soo, Audrey

AU - Rein, Reet

AU - Kadastik-Eerme, Liis

AU - Puusepp, Sanna

AU - Reinson, Karit

AU - Tomberg, Tiiu

AU - Hanagasi, Hasmet

AU - Gasser, Thomas

AU - Bhatia, Kailash P.

AU - Kurian, Manju A.

AU - Lohmann, Ebba

AU - Õunap, Katrin

AU - Rosenmund, Christian

AU - Südhof, Thomas C.

AU - Wood, Nicholas W.

AU - Krainc, Dimitri

AU - Acuna, Claudio

PY - 2021/4/1

Y1 - 2021/4/1

N2 - 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.

AB - 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.

UR - https://doi.org/10.1172/JCI140625

U2 - 10.1172/JCI140625

DO - 10.1172/JCI140625

M3 - SCORING: Journal article

VL - 131

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 7

M1 - e140625

ER -