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Lookup NU author(s): Dr Brian Wilson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 by the authors.Hyperekplexia (OMIM 149400), a sensorimotor syndrome of perinatal clinical relevance, causes newborns to display an energic startle reflex in response to certain trivial stimuli. This condition can be lethal due to apnea episodes. The disease is caused by a blockade of glycinergic neurotransmission. Glycinergic interneurons preserve their identity by the activity of the surface glycine transporter GlyT2, which supplies glycine to presynaptic terminals to maintain glycine content in synaptic vesicles. Loss-of-function mutations in the GlyT2 gene (SLC6A5) cause a presynaptic form of human hyperekplexia. Here, we describe a new GlyT2 variant found in an infantile patient diagnosed with hyperekplexia. A missense mutation in the open reading frame of the GlyT2 gene inherited in homozygosity caused the substitution G449E in a residue highly conserved across the phylogenetic scale. The sequences of the glycine receptor genes GLRA1 and GLRB did not show abnormalities. We expressed the recombinant GlyT2 variant in heterologous cells and analyzed its pathogenic mechanism. The transporter was totally inactive, behaving as a bona fide loss-of-function mutant. Furthermore, the mutation promoted the abnormal insertion of the protein into the membrane, leading to its large incorporation into lipid rafts. However, there was no apparent alteration of wild-type trafficking upon mutant coexpression, as the mutant was prematurely degraded from the endoplasmic reticulum. Rescue with chemical chaperones was not possible for this mutant. Proteomics demonstrated that the expression of the mutant induced the unfolded protein response and interfered with raft-dependent processes. Therefore, the new variant causes a loss of function regarding GlyT2 activity but a gain of function as a cell proteostasis disturber.
Author(s): Sarmiento-Jimenez J, Felipe R, Nunez E, Ferrando-Munoz A, Benito-Munoz C, Gago F, Vazquez J, Camafeita E, Clement E, Wilson B, Lopez-Corcuera B
Publication type: Article
Publication status: Published
Journal: International Journal of Molecular Sciences
Year: 2025
Volume: 26
Issue: 14
Online publication date: 14/07/2025
Acceptance date: 08/07/2025
Date deposited: 04/08/2025
ISSN (print): 1661-6596
ISSN (electronic): 1422-0067
Publisher: MDPI
URL: https://doi.org/10.3390/ijms26146753
DOI: 10.3390/ijms26146753
Data Access Statement: The datasets generated and/or analyzed during the current study are not publicly available due to individual privacy, but some data are available from the corresponding author on reasonable request. Proteomic data are available via ProteomeXchange with the identifier PXD061845.
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