Homozygous Bzrap1 Mutations Cause Autosomal Recessive Dystonia

Objective: To report the identification of bi-allelic mutations in BZRAP1, encoding the active zone (AZ) protein RIM-binding protein 1 (RBP1), as a novel cause of dystonia. Background: Dystonia is characterized by excessive muscle contractions leading to abnormal involuntary movements and postures. While the precise functional neuroanatomy and pathophysiological molecular events of dystonia are unclear, abnormal synaptic homeostasis has been observed in several models of dystonia. Design/Methods: We studied 3 pedigrees using homozygosity mapping and whole-exome sequencing and independently identified homozygous BZRAP1 mutations as the likely genetic cause of dystonia in our patients. We characterized the motor phenotype and brain pathology of BZRAP1-KO and Purkinje cells (PC)-only BZRAP1-KO mice. To directly test how the mutation p.Gly1808Ser impacts synaptic function, we measured its effect on neurotransmission in vitro. Results: 2 homozygous truncating BZRAP1 mutations (p.Ala180Profs*8 and p.Gln817*) were found in 4 subjects from 2 families. These cases all presented in teenage years with progressive generalized dystonia with prominent involvement of the cranial and laryngeal muscles and progressive cerebellar atrophy. A homozygous missense variant (p.Gly1808Ser) was identified in three family members with a milder phenotype, consisting of adult-onset segmental dystonia. BZRAP1-KO mice showed several motor abnormalities, including increased spontaneous locomotion, abnormal beam-walking, dystonic clasping of hindlimbs and a pathological motor response to cholinergic stimulation. This motor phenotype was partially recapitulated by selective BZRAP1 KO in PC. BZRAP1-KO did not affect cerebellar volume, but impacted PC dendritic morphology. Analysis of the p.Gly1808Ser variant showed a gain-of-function effect on neurotransmitter release through enhanced presynaptic calcium entry. Conclusions: We report bi-allelic BZRAP1 mutations, both loss- and gain-of-function, in patients with different forms of dystonia. RBPs mediate tethering of voltage-gated Ca2+ channels to the AZ, ensuring fidelity of synaptic vesicle release in response to action potentials. Our results demonstrate a direct link between the dysfunction of the presynaptic machinery and dystonia pathogenesis. Disclosure: Dr. Mencacci has nothing to disclose. Dr. Brockmann has nothing to disclose. Dr. Pajusalu has nothing to disclose. Dr. Atasu has nothing to disclose. Dr. Gonzalez Latapi has nothing to disclose. Dr. Schwake has nothing to disclose. Dr. Balint has nothing to disclose. Dr. Papandreou has nothing to disclose. Dr. Pittman has nothing to disclose. Dr. Simon-Sanchez has nothing to disclose. Dr. Wiethoff has nothing to disclose. Dr. Warner has nothing to disclose. Dr. Kurian has nothing to disclose. Dr. Gasser has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with MedUpdate, Novartis, Teva, and UCB Pharma. Dr. Gasser has received personal compensation in an editorial capacity for Chairman of the Scientific Advisory Board of the “Joint Programming for Neurodegenerative Diseases” program, funded by the European Commission. Dr. Gasser has received research support from German Research Foundation, German Federal Ministry of Education and Research, the European Commission, the Helmholtz Association, and the Michael J. Fox Foundation. Dr. Lohmann has nothing to disclose. Dr. Ounap has nothing to disclose. Dr. Bhatia has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen, Allergan, Cavion, Bial, and GE. Dr. Bhatia has received personal compensation in an editorial capacity for MDS. Dr. Rosenmund has nothing to disclose. Dr. Sudhof has nothing to disclose. Dr. Wood has nothing to disclose. Dr. Krainc has nothing to disclose. Dr. Acuna has nothing to disclose.