期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 22, 页码 -出版社
MDPI
DOI: 10.3390/ijms21228578
关键词
inherited metabolic disease; succinic semialdehyde dehydrogenase deficiency; γ -amino butyric acid; γ -hydroxybutyrate; mutational spectrum
资金
- Dietmar Hopp Foundation (St. Leon Rot, Germany)
- SSADH Defizit e.V.
- Physician Scientist Program at Ruprecht Karls University Heidelberg, Faculty of Medicine
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.
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