Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia
Niccolò E. Mencacci, … , Dimitri Krainc, Claudio Acuna
Niccolò E. Mencacci, … , Dimitri Krainc, Claudio Acuna
Published February 4, 2021
Citation Information: J Clin Invest. 2021;131(7):e140625. https://doi.org/10.1172/JCI140625.
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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.

Authors

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

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Figure 1

Pedigrees, genetic findings, and radiological features of subjects with pathogenic TSPOAP1/RIMBP1 variants.

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Pedigrees, genetic findings, and radiological features of subjects with ...
(A) Top: Pedigrees and variant status of affected (closed symbols) and healthy (open symbols) members of the 3 families with biallelic TSPOAP1 pathogenic variants. Bottom: Sanger sequencing validation of the variants and schematic representation of the variant effect on protein-coding sequence. W, wild-type alleles; M, mutant alleles. (B) Brain MRI sagittal T1-weighted images of subjects A-II.1 (age 28), A-II.2 (age 23), A-II.4 (age 13), and B-II.1 (age 17), demonstrating cerebellar atrophy with a predominance of the vermis in all 4 subjects carrying homozygous loss-of-function variants. (C) Cartoon illustrating the molecular interactions of RIM-binding proteins (RIMBPs) at the presynaptic active zone. RIMBPs bind with the first SH3 domain to Bassoon, with the FN3 domains to calcium-activated potassium channels (BK), and with the second and third SH3 domain to voltage-gated calcium-channels (Ca2+) and RIM proteins. (D) Schematic representation of RIMBP1 structure including protein domains and localization of the identified variants. The amino acid residue Gly1808 is located in the C-terminal SH3 domain and shows complete evolutionary conservation across all species and in the human protein homolog RIMBP2. Asterisks indicate invariant residues (full conservation), whereas colons and periods represent strong and moderate similarities, respectively.