Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1

Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital Heidelberg, 69120 Heidelberg, Germany

Institute of Biochemistry, Medical Faculty, University of Giessen, 35392 Giessen, Germany

Department of Neuroscience, Biomedicine and Movement, Section of Biological Chemistry, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy

⁴

Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100 Varese, Italy

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to the manuscript.

Int. J. Mol. Sci. 2020, 21(22), 8578; https://doi.org/10.3390/ijms21228578

Received: 23 October 2020 / Revised: 9 November 2020 / Accepted: 11 November 2020 / Published: 13 November 2020

(This article belongs to the Special Issue Molecular Research on Inherited Disorders)

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Abstract

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare, monogenic disorder affecting the degradation of the main inhibitory neurotransmitter γ-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 γ-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. View Full-Text

Keywords: inherited metabolic disease; succinic semialdehyde dehydrogenase deficiency; γ-amino butyric acid; γ-hydroxybutyrate; mutational spectrum

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MDPI and ACS Style

Brennenstuhl, H.; Didiasova, M.; Assmann, B.; Bertoldi, M.; Molla, G.; Jung-Klawitter, S.; Kuseyri Hübschmann, O.; Schröter, J.; Opladen, T.; Tikkanen, R. Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1. Int. J. Mol. Sci. 2020, 21, 8578. https://doi.org/10.3390/ijms21228578

AMA Style

Brennenstuhl H, Didiasova M, Assmann B, Bertoldi M, Molla G, Jung-Klawitter S, Kuseyri Hübschmann O, Schröter J, Opladen T, Tikkanen R. 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. 2020; 21(22):8578. https://doi.org/10.3390/ijms21228578

Chicago/Turabian Style

Brennenstuhl, Heiko, Miroslava Didiasova, Birgit Assmann, Mariarita Bertoldi, Gianluca Molla, Sabine Jung-Klawitter, Oya Kuseyri Hübschmann, Julian Schröter, Thomas Opladen, and Ritva Tikkanen. 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, no. 22: 8578. https://doi.org/10.3390/ijms21228578

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Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1

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