A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog.

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; König, Florian; Van Winkle, Thomas J; O'Brien, Dennis; Roos, B; Matiasek, Kaspar; Jagannathan, Vidya; Drögemüller, Cord; Mansour, Tamer A; ... (2020). A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog. Genes, 11(9) MDPI, Molecular Diversity Preservation International 10.3390/genes11091033

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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.

Item Type:

Journal Article (Original Article)


05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Letko, Anna; Jagannathan, Vidya and Drögemüller, Cord


500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health




MDPI, Molecular Diversity Preservation International




Cord Drögemüller

Date Deposited:

08 Sep 2020 14:36

Last Modified:

08 Sep 2020 14:36

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

4-hydroxybutyric acid ALDH5A1 GABA GWAS SSADHD encephalopathy inborn error of metabolism inherited precision medicine succinic semialdehyde whole-genome sequencing





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