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Functional Characterization of a Spectrum of Genetic Variants in a Family with Succinic Semialdehyde Dehydrogenase Deficiency.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2024 May 11; Vol. 25 (10). Date of Electronic Publication: 2024 May 11. - Publication Year :
- 2024
-
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 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 <superscript>+</superscript> 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.
- Subjects :
- Female
Humans
Male
Genetic Variation
Mutation
Pedigree
Protein Folding
Amino Acid Metabolism, Inborn Errors genetics
Amino Acid Metabolism, Inborn Errors metabolism
Amino Acid Metabolism, Inborn Errors pathology
Developmental Disabilities genetics
Developmental Disabilities metabolism
Developmental Disabilities pathology
Succinate-Semialdehyde Dehydrogenase deficiency
Succinate-Semialdehyde Dehydrogenase genetics
Succinate-Semialdehyde Dehydrogenase chemistry
Succinate-Semialdehyde Dehydrogenase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 25
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 38791277
- Full Text :
- https://doi.org/10.3390/ijms25105237