Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia
Standard
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, Jahrgang 131, Nr. 7, e140625, 01.04.2021.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
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 -