Efthymiou, Stephanie;
Han, Wenyan;
Ilyas, Muhammad;
Li, Jun;
Yu, Yichao;
Scala, Marcello;
Malintan, Nancy T;
... Houlden, Henry; + view all
(2024)
Human mutations in SLITRK3 implicated in GABAergic synapse development in mice.
Frontiers in Molecular Neuroscience
, 17
, Article 1222935. 10.3389/fnmol.2024.1222935.
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Abstract
This study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients' SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.
| Type: | Article |
|---|---|
| Title: | Human mutations in SLITRK3 implicated in GABAergic synapse development in mice |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fnmol.2024.1222935 |
| Publisher version: | https://doi.org/10.3389/fnmol.2024.1222935 |
| Language: | English |
| Additional information: | COPYRIGHT © 2024 Efthymiou, Han, Ilyas, Li, Yu, Scala, Malintan, Ilyas, Vavouraki, Mankad, Maroofian, Rocca, Salpietro, Lakhani, Mallack, Palculict, Li, Zhang, Zafar, Rana, Takashima, Matsunaga, Manzoni, Striano, Lythgoe, Aruga, Lu and Houlden. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | GABAergic synapse development, NGS - next generation sequencing, SLITRK3, epilepsy, global developmental delay, inhibitory synaptic transmission |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10189540 |
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