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

• Published in: Genes Vol. 11; no. 9; p. 1033
• Main Authors: 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, Vidhya, Drögemüller, Cord, Mansour, Tamer A, Brown, C Titus, Bannasch, Danika L
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 02.09.2020; MDPI
• Subjects: Aciduria; Aldehyde dehydrogenase; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Sequence; Animal models; Animals; Atrophy; Brain - metabolism; Cerebrospinal fluid; Cerebrospinal Fluid - metabolism; Convulsions & seizures; Deoxyribonucleic acid; Developmental Disabilities - genetics; Diagnostic tests; Disease Models, Animal; DNA; Dog diseases; Dogs; Epilepsy; Female; gamma-Aminobutyric Acid - genetics; Genetic analysis; Genetic aspects; Genetic Testing - methods; Genetic variation; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Health aspects; Inborn errors of metabolism; Magnetic resonance imaging; Male; Metabolic Networks and Pathways - genetics; Metabolic pathways; Metabolism; Mutation, Missense - genetics; Necropsy; Nervous system; Neuroimaging; Pathology; Phenotype; Phenotypes; Seizures; Seizures - genetics; Seizures - metabolism; Succinate-semialdehyde dehydrogenase; Succinate-Semialdehyde Dehydrogenase - deficiency; Succinate-Semialdehyde Dehydrogenase - genetics; Urine; Veterinary medicine; Whole genome sequencing; γ-Aminobutyric acid; γ-Hydroxybutyric acid; United States; Los Angeles California; California; United States > US; Germany; 4-hydroxybutyric acid; ALDH5A1; GWAS; succinic semialdehyde; inherited; whole-genome sequencing; GABA; precision medicine; inborn error of metabolism; SSADHD; encephalopathy
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes11091033

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 ( ) gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). 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. -related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies.