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 3

Cerebellar abnormalities in RIMBP1-KO mice.

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Cerebellar abnormalities in RIMBP1-KO mice. (A) Gross anatomy of the cer...
(A) Gross anatomy of the cerebellum. Left: Dorsal view of RIMBP1-WT and RIMBP1-KO brains. Middle: Confocal image of a parasagittal section stained with DAPI and anti-calbindin antibodies (green). Right: Summary plot of cerebellar volume (left) and of Purkinje cell (PC) number (right). Scale bars: 0.8 cm (left) and 20 μm (right). (B) Structure of PC dendrites in RIMBP1 control and mutant mice. Left: Low-magnification images of parasagittal sections stained with anti-calbindin antibodies. Middle: High-magnification images (single optical sections) of the areas indicated with the white boxes on the left displaying outer (0%–40%) and inner (40%–80%) PC dendritic domains. Right, top: Summary graphs of calbindin coverage (area) in different PC dendritic domains. Right, bottom: Summary graphs of calbindin intensity signal in the same PC dendritic domains. Scale bars: 1 mm (left) and 40 μm (right). (C) Organization of parallel fiber synapses. Left: Representative confocal images of cerebellar sections from a RIMBP1-WT mouse. Middle: Representative images from a littermate RIMBP1-KO mouse. Sections were stained for calbindin (green, to label PCs), for vGluT1 (red, to visualize parallel fibers), and with DAPI (blue, cell nuclei). Right: Summary graphs of vGluT1 intensity for the outermost and innermost PC dendritic domains in RIMBP1-WT mice and -KO littermates. Scale bar: 40 μm. (D and E) Same as in C but for climbing fiber synapses stained with anti-vGluT2 antibodies. In this case, the density (D, right) and the size (E) of vGluT2-containing puncta were compared. Scale bar: 40 μm. (F) Levels of key proteins in cerebellar lysates. Left: Representative blots. Right: Summary plots of band intensity values normalized to Tuj1. Data are presented as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by Student’s t test. NS, not significant. Number of experiments (mice/sections): (A) Left: 5 WT, 6 KO; Right: 6/62 WT, 6/47 KO; (B) Intensity: 6/59 WT, 6/64 KO; Area: 6/57 WT, 6/60 KO; (C) vGluT1: 6/59 WT, 6/56 KO; (D and E) vGluT2: 6/54 WT, 6/60 KO; (F) 10 RIMBP+/+, 10 RIMBP–/–.