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

Gianluca Molla¹  Julian Schröter²  Thomas Opladen²  Heiko Brennenstuhl²  Oya Kuseyri Hübschmann²  Birgit Assmann²  Sabine Jung-Klawitter²  Mariarita Bertoldi³  Miroslava Didiasova⁴  Ritva Tikkanen⁴ 

[1] Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100 Varese, Italy;Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital Heidelberg, 69120 Heidelberg, Germany;Department of Neuroscience, Biomedicine and Movement, Section of Biological Chemistry, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy;Institute of Biochemistry, Medical Faculty, University of Giessen, 35392 Giessen, Germany;

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

DOI  :  10.3390/ijms21228578

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown