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A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog
| Content Provider | MDPI |
|---|---|
| Author | Florian, König O’Brien, Dennis Cord, Drögemüller Vernau, Karen M. Struys, Eduard Letko, Anna Woolard, Kevin D. Aguilar, Miriam Brown, Emily A. Cissell, Derek D. Dickinson, Peter J. Shelton, G. Diane Broome, Michael R. Gibson, K. Michael Pearl, Phillip L. Winkle, Thomas J. Van Roos, B. Matiasek, Kaspar Jagannathan, Vidhya Mansour, Tamer A. Brown, C. Titus Bannasch, Danika L. |
| Copyright Year | 2020 |
| Description | Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions. Cerebral cortical atrophy with vacuolation (status spongiosus) was noted on necropsy. Genome-wide association study of 7 affected and 28 normal Salukis revealed a genome-wide significantly associated region on CFA 35. Whole-genome sequencing of three confirmed cases from three different litters revealed a homozygous missense variant within the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). ALDH5A1 encodes a succinic semialdehyde dehydrogenase (SSADH) enzyme critical in the gamma-aminobutyric acid neurotransmitter (GABA) metabolic pathway. Metabolic screening of affected dogs showed markedly elevated gamma-hydroxybutyric acid in serum, cerebrospinal fluid (CSF) and brain, and elevated succinate semialdehyde in urine, CSF and brain. SSADH activity in the brain of affected dogs was low. Affected Saluki dogs had striking similarities to SSADH deficiency in humans although hydroxybutyric aciduria was absent in affected dogs. ALDH5A1-related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies. |
| Starting Page | 1033 |
| e-ISSN | 20734425 |
| DOI | 10.3390/genes11091033 |
| Journal | Genes |
| Issue Number | 9 |
| Volume Number | 11 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2020-09-02 |
| Access Restriction | Open |
| Subject Keyword | Genes Endocrinology and Metabolism Inborn Error of Metabolism Encephalopathy Ssadhd Aldh5a1 Gaba 4-hydroxybutyric Acid Succinic Semialdehyde Whole-genome Sequencing Precision Medicine Gwas Inherited |
| Content Type | Text |
| Resource Type | Article |
