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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Research Article Genetics Neuroscience

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 2

Motor abnormalities in RIMBP1-KO mice.

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Motor abnormalities in RIMBP1-KO mice. (A) Open-field locomotor activity...
(A) Open-field locomotor activity. Left: Locomotor activity as a function of time (bin width, 5 minutes). P value by 1-way ANOVA. Middle: Total activity in RIMBP1-WT and RIMBP1-KO mice. Right: Comparison of relative activity in the periphery (P, left) and the center (C, right) of the open field arena in control and mutant mice. (B) Beam-walk test. Left: Cumulative distribution (left) and summary graphs (right) of total time to cross the beam in RIMBP1-WT and RIMBP1-KO mice. Right: Cumulative distribution (left) and summary graphs (right) of total number of slips in RIMBP1-WT and RIMBP1 KO mice. (C) Limb-clasping test. Left: Representative pictures of a RIMBP1-WT (left) and a RIMBP1-KO (right) mouse during the tail suspension test used to measure limb clasping. Arrows highlight limb clasping in the RIMBP1-KO mouse. Left: Percentage of RIMBP1-WT and RIMBP1-KO mice displaying limb clasping in tail suspension test lasting 10, 20, or 30 seconds. Right: Clasping index in control and mutant mice tail-suspended for 10, 20, or 30 seconds. (D) Abnormal movements and postures triggered by systemic oxotremorine. Top: Examples of abnormal postures (arrows) found in RIMBP1-KO mice after oxotremorine treatment (0.01 mg/kg). Bottom, left: Time course of abnormal motor scores after oxotremorine treatment (0.01 mg/kg). Motor scores were assessed in 2-minute bins. Abnormal motor score scale: 0 = normal motor behavior, 1 = no impairment but slightly slowed movements, 2 = mild impairment with occasional abnormal postures and movements and ambulation with slow walk, 3 = moderate impairment with frequent abnormal postures and movements with limited ambulation, 4 = severe impairment with sustained abnormal postures without any ambulation or upright position. P value by 1-way ANOVA. Bottom, right: Summed abnormal motor scores recorded for 60 minutes after drug injection. Data are presented as mean ± SEM. Number of experiments: (A, right) 19 WT, 16 KO; (B) 10 WT, 10 KO; (C) 10 WT, 10 KO; (D) 9 WT, 10 KO. *P < 0.05; ***P < 0.001 by 1-way ANOVA or Student’s t test (in bar graphs in A–D). NS, not significant.