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

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 <i>ALDH5A1</i> gene that cause an enzymatic dysfunction of succinic semialdehyde...

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Main Authors:	Heiko Brennenstuhl, Miroslava Didiasova, Birgit Assmann, Mariarita Bertoldi, Gianluca Molla, Sabine Jung-Klawitter, Oya Kuseyri Hübschmann, Julian Schröter, Thomas Opladen, Ritva Tikkanen
Format:	Article
Language:	English
Published:	MDPI AG 2020-11-01
Series:	International Journal of Molecular Sciences
Subjects:	inherited metabolic disease succinic semialdehyde dehydrogenase deficiency γ-amino butyric acid γ–hydroxybutyrate mutational spectrum
Online Access:	https://www.mdpi.com/1422-0067/21/22/8578

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spelling	doaj-b42e97c8a9b2402793f8694b5b45732f2020-11-25T04:09:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-01218578857810.3390/ijms21228578Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of <i>ALDH5A1</i>Heiko Brennenstuhl0Miroslava Didiasova1Birgit Assmann2Mariarita Bertoldi3Gianluca Molla4Sabine Jung-Klawitter5Oya Kuseyri Hübschmann6Julian Schröter7Thomas Opladen8Ritva Tikkanen9Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital Heidelberg, 69120 Heidelberg, GermanyInstitute of Biochemistry, Medical Faculty, University of Giessen, 35392 Giessen, GermanyDepartment of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of Neuroscience, Biomedicine and Movement, Section of Biological Chemistry, University of Verona, Strada Le Grazie, 8, 37134 Verona, ItalyDepartment of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100 Varese, ItalyDepartment of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital Heidelberg, 69120 Heidelberg, GermanyDepartment of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital Heidelberg, 69120 Heidelberg, GermanyInstitute of Biochemistry, Medical Faculty, University of Giessen, 35392 Giessen, GermanySuccinic 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 <i>ALDH5A1</i> 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)<sup>+</sup> 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 <i>ALDH5A1</i> to identify mutational hotspots.https://www.mdpi.com/1422-0067/21/22/8578inherited metabolic diseasesuccinic semialdehyde dehydrogenase deficiencyγ-amino butyric acidγ–hydroxybutyratemutational spectrum
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Heiko Brennenstuhl Miroslava Didiasova Birgit Assmann Mariarita Bertoldi Gianluca Molla Sabine Jung-Klawitter Oya Kuseyri Hübschmann Julian Schröter Thomas Opladen Ritva Tikkanen
spellingShingle	Heiko Brennenstuhl Miroslava Didiasova Birgit Assmann Mariarita Bertoldi Gianluca Molla Sabine Jung-Klawitter Oya Kuseyri Hübschmann Julian Schröter Thomas Opladen Ritva Tikkanen Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of <i>ALDH5A1</i> International Journal of Molecular Sciences inherited metabolic disease succinic semialdehyde dehydrogenase deficiency γ-amino butyric acid γ–hydroxybutyrate mutational spectrum
author_facet	Heiko Brennenstuhl Miroslava Didiasova Birgit Assmann Mariarita Bertoldi Gianluca Molla Sabine Jung-Klawitter Oya Kuseyri Hübschmann Julian Schröter Thomas Opladen Ritva Tikkanen
author_sort	Heiko Brennenstuhl
title	Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of <i>ALDH5A1</i>
title_short	Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of <i>ALDH5A1</i>
title_full	Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of <i>ALDH5A1</i>
title_fullStr	Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of <i>ALDH5A1</i>
title_full_unstemmed	Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of <i>ALDH5A1</i>
title_sort	succinic semialdehyde dehydrogenase deficiency: in vitro and in silico characterization of a novel pathogenic missense variant and analysis of the mutational spectrum of <i>aldh5a1</i>
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1661-6596 1422-0067
publishDate	2020-11-01
description	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 <i>ALDH5A1</i> 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)<sup>+</sup> 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 <i>ALDH5A1</i> to identify mutational hotspots.
topic	inherited metabolic disease succinic semialdehyde dehydrogenase deficiency γ-amino butyric acid γ–hydroxybutyrate mutational spectrum
url	https://www.mdpi.com/1422-0067/21/22/8578
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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 <i>ALDH5A1</i>

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