Journal article

Publication year: 2020

Journal: International Journal of Molecular Sciences

Volume number: 21

Issue number: 22

eISSN: 1422-0067

Open access status: Gold

DOI Link: https://doi.org/10.3390/ijms21228578

Publisher: MDPI

Abstract: 
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter gamma-amino butyric acid (GABA). Pathogenic variants in the ALDH5A1 gene that cause an enzymatic dysfunction of succinic semialdehyde dehydrogenase (SSADH) lead to an accumulation of potentially toxic metabolites, including gamma-hydroxybutyrate (GHB). Here, we present a patient with a severe phenotype of SSADHD caused by a novel genetic variant c.728T > C that leads to an exchange of leucine to proline at residue 243, located within the highly conserved nicotinamide adenine dinucleotide (NAD)(+) binding domain of SSADH. Proline harbors a pyrrolidine within its side chain known for its conformational rigidity and disruption of protein secondary structures. We investigate the effect of this novel variant in vivo, in vitro, and in silico. We furthermore examine the mutational spectrum of all previously described disease-causing variants and computationally assess all biologically possible missense variants of ALDH5A1 to identify mutational hotspots.

Harvard Citation style: Brennenstuhl, H., Didiasova, M., Assmann, B., Bertoldi, M., Molla, G., Jung-Klawitter, S., et al. (2020) Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1, International Journal of Molecular Sciences, 21(22), Article 8578. https://doi.org/10.3390/ijms21228578

APA Citation style: Brennenstuhl, H., Didiasova, M., Assmann, B., Bertoldi, M., Molla, G., Jung-Klawitter, S., Kuseyri Hübschmann, O., Schröter, J., Opladen, T., & Tikkanen, R. (2020). Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1. International Journal of Molecular Sciences. 21(22), Article 8578. https://doi.org/10.3390/ijms21228578