Dual Role of Dysfunctional Asc-1 Transporter in Distinct Human Pathologies, Human Startle Disease, and Developmental Delay
Open accessAbstract
Human startle disease is associated with mutations in distinct genes encoding glycine receptors, transporters or interacting proteins at glycinergic synapses in spinal cord and brainstem. However, a significant number of diagnosed patients does not carry a mutation in the common genes GLRA1,GLRB, and SLC6A5. Recently, studies on solute carrier 7 subfamily 10 (SLC7A10; Asc-1, alanine-serine-cysteine transporter) knock-out (KO) mice displaying a startle disease-like phenotype hypothesized that this transporter might represent a novel candidate for human startle disease. Here, we screened 51 patients from our patient cohort negative for the common genes and found three exonic (one missense, two synonymous), seven intronic, and single nucleotide changes in the 5′ and 3′ untranslated regions (UTRs) in Asc-1. The identified missense mutation Asc-1 G307R from a patient with startle disease and developmental delay was investigated in functional studies. At the molecular level, the mutation Asc-1 G307R did not interfere with cell-surface expression, but disrupted glycine uptake. Substitution of glycine at position 307 to other amino acids, e.g., to alanine or tryptophan did not affect trafficking or glycine transport. By contrast, G307K disrupted glycine transport similar to the G307R mutation found in the patient. Structurally, the disrupted function in variants carrying positively charged residues can be explained by local structural rearrangements because of the large positively charged side chain. Thus, our data suggest that SLC7A10 may represent a rare but novel gene associated with human startle disease and developmental delay.
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SLC7A10 is a potential rare gene associated with human startle disease and developmental delay.
“Although the function of neutral amino acid transporter SLC7A10 in CNS remains to be elucidated, studies with SLC7A10 knock-out mice and dysfunctional SLC7A10 mutations reveal that SLC7A10 is a potential rare gene associated with human startle disease and developmental delay [76, 77].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [77]
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- Authors
- Drehmann, P., Milanos, S., Schaefer, N., Kasaragod, V. B., Herterich, S., Holzbach-Eberle, U., Harvey, R. J., & Villmann, C.
- Affiliations
- University of Würzburg (DE)
- MRC Laboratory of Molecular Biology (GB)
- University of the Sunshine Coast (AU)
- Corresponding author
- Villmann, Carmen
- Venue
- eneuro
- Publisher
- Society for Neuroscience
- Published
- 2023-10-30
- Volume
- 10
- Issue
- 11
- Pages
- ENEURO.0263-23.2023
- ISSN
- 2373-2822 (ISSN-L)
- PMC
- PMC10668224
- OpenAlex
- W4388035555
- Cited by
- 9
- References
- 39
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- eNeuro (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (VI586)
- Scientia
- Willy Robert Pitzer Stiftung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- glycine uptake, developmental delay, missense mutations, glycinergic synapses, spinal cord, brainstem, protein structural rearrangement
- MeSH terms
- Alanine, Animals, Glycine, Humans, Mutation, Receptors, Glycine, Mutation, Missense, Glycine Plasma Membrane Transport Proteins, Mice
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