Version 1
: Received: 4 April 2024 / Approved: 4 April 2024 / Online: 4 April 2024 (09:12:15 CEST)
How to cite:
Didiasova, M.; Cesaro, S.; Feldhoff, S.; Bettin, I.; Tiegel, N.; Füssgen, V.; Bertoldi, M.; Tikkanen, R. Functional Characterization of a Spectrum of Genetic Variants in a Family With Succinic Semialdehyde Dehydrogenase Deficiency. Preprints2024, 2024040360. https://doi.org/10.20944/preprints202404.0360.v1
Didiasova, M.; Cesaro, S.; Feldhoff, S.; Bettin, I.; Tiegel, N.; Füssgen, V.; Bertoldi, M.; Tikkanen, R. Functional Characterization of a Spectrum of Genetic Variants in a Family With Succinic Semialdehyde Dehydrogenase Deficiency. Preprints 2024, 2024040360. https://doi.org/10.20944/preprints202404.0360.v1
Didiasova, M.; Cesaro, S.; Feldhoff, S.; Bettin, I.; Tiegel, N.; Füssgen, V.; Bertoldi, M.; Tikkanen, R. Functional Characterization of a Spectrum of Genetic Variants in a Family With Succinic Semialdehyde Dehydrogenase Deficiency. Preprints2024, 2024040360. https://doi.org/10.20944/preprints202404.0360.v1
APA Style
Didiasova, M., Cesaro, S., Feldhoff, S., Bettin, I., Tiegel, N., Füssgen, V., Bertoldi, M., & Tikkanen, R. (2024). Functional Characterization of a Spectrum of Genetic Variants in a Family With Succinic Semialdehyde Dehydrogenase Deficiency. Preprints. https://doi.org/10.20944/preprints202404.0360.v1
Chicago/Turabian Style
Didiasova, M., Mariarita Bertoldi and Ritva Tikkanen. 2024 "Functional Characterization of a Spectrum of Genetic Variants in a Family With Succinic Semialdehyde Dehydrogenase Deficiency" Preprints. https://doi.org/10.20944/preprints202404.0360.v1
Abstract
Succinic semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter γ-amino butyric acid. Pathogenic variants in the gene encoding this enzyme cause SSADH deficiency, a developmental disease manifesting as hypotonia, autism and epilepsy. SSADH deficiency patients usually have family-specific gene variants. Here, we describe a family exhibiting four different SSADH variants, Val90Ala, Cys93Phe, and His180Tyr/Asn255Asp (a double variant). We provide a structural and functional characterization of these variants and show that Cys93Phe and Asn255Asp are pathogenic variants that affect the stability of the SSADH protein. Due to impairment of the cofactor NAD+ binding, these variants show a highly reduced enzyme activity. However, Val90Ala and His180Tyr exhibit normal activity and expression. The His180Tyr/Asn255Asp variant exhibits a highly reduced activity as a recombinant species, is inactive and shows a very low expression in eukaryotic cells. A treatment with substances that support protein folding by either increasing chaperone protein expression or by chemical means was not capable of increasing the expression of the pathogenic variants of the SSADH deficiency patient. However, stabilization of the folding of pathogenic SSADH variants by other substances may provide a treatment option for this disease.
Keywords
Neurotransmitter diseases; GABA; mitochondria; protein folding; chaperones; aldehyde dehydrogenases
Subject
Medicine and Pharmacology, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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