Journal article

Publication year: 2024

Journal: International Journal of Molecular Sciences

Volume number: 25

Issue number: 10

ISSN: 1661-6596

eISSN: 1422-0067

Open access status: Gold

DOI Link: https://doi.org/10.3390/ijms25105237

Publisher: MDPI

Abstract: 
Succinic semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter gamma-amino butyric acid. Pathogenic variants in the gene encoding this enzyme cause SSADH deficiency, a developmental disease that manifests 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 the 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 did not increase 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.

Harvard Citation style: Didiasova, M., Cesaro, S., Feldhoff, S., Bettin, I., Tiegel, N., Fuessgen, V., et al. (2024) Functional Characterization of a Spectrum of Genetic Variants in a Family with Succinic Semialdehyde Dehydrogenase Deficiency, International Journal of Molecular Sciences, 25(10), Article 5237. https://doi.org/10.3390/ijms25105237

APA Citation style: Didiasova, M., Cesaro, S., Feldhoff, S., Bettin, I., Tiegel, N., Fuessgen, V., Bertoldi, M., & Tikkanen, R. (2024). Functional Characterization of a Spectrum of Genetic Variants in a Family with Succinic Semialdehyde Dehydrogenase Deficiency. International Journal of Molecular Sciences. 25(10), Article 5237. https://doi.org/10.3390/ijms25105237