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Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.

ABSTRACT: Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.

SUBMITTER: Lipstein N

PROVIDER: S-EPMC5330740 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.

Lipstein Noa N Verhoeven-Duif Nanda M NM Michelassi Francesco E FE Calloway Nathaniel N van Hasselt Peter M PM Pienkowska Katarzyna K van Haaften Gijs G van Haelst Mieke M MM van Empelen Ron R Cuppen Inge I van Teeseling Heleen C HC Evelein Annemieke M V AM Vorstman Jacob A JA Thoms Sven S Jahn Olaf O Duran Karen J KJ Monroe Glen R GR Ryan Timothy A TA Taschenberger Holger H Dittman Jeremy S JS Rhee Jeong-Seop JS Visser Gepke G Jans Judith J JJ Brose Nils N

The Journal of clinical investigation 20170213 3

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu va ...[more]

PMID: 28192369

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Project description:Background and Objectives To characterize the clinical and cognitive behavioral phenotype and brain 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of the UNC13A gene. Methods The study population included 1,409 patients with ALS without C9orf72, SOD1, TARDBP, and FUS mutations identified through a prospective epidemiologic ALS register. Control participants included 1,012 geographically matched, age-matched, and sex-matched participants. Clinical and cognitive differences between patients carrying the C/C rs12608932 genotype and those carrying the A/A + A/C genotype were assessed. A subset of patients underwent 18F-FDG-PET. Results The C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% confidence interval 1.18–2.01, p = 0.001). Patients with the C/C genotype were older, had more frequent bulbar onset, and manifested a higher rate of weight loss. In addition, they showed significantly reduced performance in the letter fluency test, fluency domain of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and story-based empathy task (reflecting social cognition). Patients with the C/C genotype had a shorter survival (median survival time, C/C 2.25 years, interquartile range [IQR] 1.33–3.92; A/A + C/C: 2.90 years, IQR 1.74–5.41; p = 0.0001). In Cox multivariable analysis, C/C genotype resulted to be an independent prognostic factor. Finally, patients with a C/C genotype had a specific pattern of hypometabolism on brain 18F-FDG-PET extending to frontal and precentral areas of the right hemisphere. Discussion C/C rs12608932 genotype of UNC13A is associated with a specific motor and cognitive/behavioral phenotype, which reflects on 18F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 variant in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.

Dataset Information

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.

Publications

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.

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