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

• Published in: The Journal of clinical investigation Vol. 131; no. 7; pp. 1 - 14
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2021
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Alleles; Amino Acid Substitution; Animals; Atrophy; Binding proteins; Biomedical research; Calcium Signaling; Calcium signalling; Care and treatment; Cerebellum; Dendrites - genetics; Dendrites - metabolism; Dendritic branching; Development and progression; Dystonia; Dystonic Disorders - genetics; Dystonic Disorders - metabolism; Families & family life; Female; Genetic aspects; Genetic variation; Health aspects; Humans; Intellectual disabilities; Male; Mice; Mice, Knockout; Motor task performance; Movement disorders; Mutation, Missense; Neural networks; Neural transmission; Neurotransmission; Pathogenesis; Proteins; Purkinje Cells - metabolism; Synapses; Synaptic Transmission; United States; Genetics; Neuroscience; Genetic diseases; Movement disorders; Synapses
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI140625

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.