Single nucleotide variants in UNC13C associated with neurodevelopmental disorders affect ethanol sensitivity in Drosophila

UNC13s are presynaptic proteins essential for neurotransmitter release at chemical synapses. In this study, we present eleven patients from nine families with severe neurodevelopmental impairments, who carry rare, biallelic <i>UNC13C</i> single-nucleotide variants (SNVs). Six missense variants, each identified in compound heterozygosity in one of three of these patients, were introduced into the <i>Drosophila melanogaster</i> ortholog <i>unc13</i> using a previously established CRISPR/Cas9-based method for rapid and scarless genomic modifications, hypothesising that they underlie the observed clinical manifestations. However, none of the introduced mutations influenced Mendelian ratios, negative geotaxis, or lifespan of the fruit flies. Interestingly, two variants located outside the gene regions encoding known UNC13C domains caused a decreased ethanol sensitivity in <i>Drosophila</i>, while the Thr1729Met substitution within the C<sub>1</sub> domain resulted in increased ethanol sensitivity. Molecular dynamics simulations of the latter mutant gene product suggested that the altered protein conformation enhances exposure of the ethanol-binding site, thereby increasing sensitivity to ethanol. These findings reinforce previous evidence highlighting the critical role of the C<sub>1</sub> domain in ethanol sensitivity. Given the involvement of the C<sub>1</sub> domain in synaptic plasticity this result might implicate an influence of the Thr1729Met on synaptic function.

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Publication Details

Journal
Biochemistry and Biophysics Reports
Published
2025-11-28
DOI
https://doi.org/10.1016/j.bbrep.2025.102375
Primary Topic
Neuroscience and Neuropharmacology Research
Type
article
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Single nucleotide variants in UNC13C associated with neurodevelopmental disorders affect ethanol sensitivity in Drosophila

Joydip Das, Alexandre Reymond, Elizabeth Mizerik, Nicole Scholz et al.
Biochemistry and Biophysics Reports
Neuroscience and Neuropharmacology Research
article

Single nucleotide variants in UNC13C associated with neurodevelopmental disorders affect ethanol sensitivity in Drosophila

Joydip Das, Alexandre Reymond, Elizabeth Mizerik, Nicole Scholz, Eva H. Brilstra, Gregg Roman, Sonja Neuser, Anita M. Rauch, Achmed Mrestani, Koen L.I. van Gassen, Matthew Hoi Kin Chau, Tahsin Stefan Barakat, Jill Anne Rosenfeld, Duha Fahham, Anaïs Begemann, Tobias Langenhan, Anne-Kristin Dahse, Netra Prasad Neupane, Jonathan Rips, Dmitrij Ljaschenko, P Olivier, Nicola Brunetti‐Pierri, Rami Abou Jamra, Swati Srivastava, Jérémie Mortreux, Gaetano Terrone, Katharina J Götze, Xi Luo, Gaurav Shrestha, Franz Müller, Katharina Steindl
article en

Abstract

UNC13s are presynaptic proteins essential for neurotransmitter release at chemical synapses. In this study, we present eleven patients from nine families with severe neurodevelopmental impairments, who carry rare, biallelic <i>UNC13C</i> single-nucleotide variants (SNVs). Six missense variants, each identified in compound heterozygosity in one of three of these patients, were introduced into the <i>Drosophila melanogaster</i> ortholog <i>unc13</i> using a previously established CRISPR/Cas9-based method for rapid and scarless genomic modifications, hypothesising that they underlie the observed clinical manifestations. However, none of the introduced mutations influenced Mendelian ratios, negative geotaxis, or lifespan of the fruit flies. Interestingly, two variants located outside the gene regions encoding known UNC13C domains caused a decreased ethanol sensitivity in <i>Drosophila</i>, while the Thr1729Met substitution within the C<sub>1</sub> domain resulted in increased ethanol sensitivity. Molecular dynamics simulations of the latter mutant gene product suggested that the altered protein conformation enhances exposure of the ethanol-binding site, thereby increasing sensitivity to ethanol. These findings reinforce previous evidence highlighting the critical role of the C<sub>1</sub> domain in ethanol sensitivity. Given the involvement of the C<sub>1</sub> domain in synaptic plasticity this result might implicate an influence of the Thr1729Met on synaptic function.

Biochemistry and Biophysics ReportsVol. 45
Leipzig University of Applied Sciences (DE), Chinese University of Hong Kong (HK), Baylor College of Medicine (US), Utrecht University (NL), Hebrew University of Jerusalem (IL), University of Zurich (CH), Hadassah Medical Center (IL), Erasmus MC (NL), University Medical Center Utrecht (NL), Jerusalem Multidisciplinary College (IL), University of Mississippi (US), Laboratoire de Biologie et Modélisation de la Cellule (FR), Federico II University Hospital (IT), University Hospital Leipzig (DE), Hôpital Purpan (FR), Texas Children's Hospital (US), Scuola Superiore Meridionale (IT), Telethon Institute Of Genetics And Medicine (IT), Baylor Genetics (US), University of Houston (US), Leipzig University (DE), University of Lausanne (CH)
Deutsche Forschungsgemeinschaft, ZonMw, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Jung-Stiftung für Wissenschaft und Forschung, Universität Leipzig, National Institutes of Health
Openalex Percentile: Top 60%
Neuroscience and Neuropharmacology Research
DOIOpen Access PDFOpenAlex
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