A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog
| Autor: | Dennis P. O'Brien, Vidhya Jagannathan, Karen M. Vernau, Eduard A. Struys, Phillip L. Pearl, C. Titus Brown, Kevin D. Woolard, G. Diane Shelton, Tamer A. Mansour, Cord Drögemüller, Anna Letko, Thomas J. Van Winkle, Danika L. Bannasch, Derek D. Cissell, Emily A. Brown, K. Michael Gibson, Kaspar Matiasek, Florian König, Peter J Dickinson, Birthe Roos, Miriam Aguilar, Michael R Broome |
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| Přispěvatelé: | Clinical chemistry, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Succinic semialdehyde dehydrogenase deficiency Male Developmental Disabilities Succinic semialdehyde chemistry.chemical_compound GABA 0302 clinical medicine Cerebrospinal fluid Missense mutation GWAS 2.1 Biological and endogenous factors Aetiology 610 Medicine & health Genetics (clinical) gamma-Aminobutyric Acid Cerebrospinal Fluid SSADHD 630 Agriculture Inborn Errors Brain encephalopathy 4-hydroxybutyric acid Phenotype whole-genome sequencing Neurological 590 Animals (Zoology) Female Succinate-Semialdehyde Dehydrogenase Metabolic Networks and Pathways Biotechnology medicine.medical_specialty lcsh:QH426-470 ALDH5A1 precision medicine Encephalopathy Mutation Missense Biology Article 03 medical and health sciences Dogs Rare Diseases Seizures Internal medicine medicine inborn error of metabolism succinic semialdehyde Genetics Aldehyde dehydrogenase 5 family member A1 Animals Amino Acid Sequence Genetic Testing Amino Acid Metabolism Inborn Errors Animal Human Genome Neurosciences medicine.disease Hyperintensity inherited Brain Disorders Amino Acid Metabolism lcsh:Genetics Disease Models Animal 030104 developmental biology Endocrinology Orphan Drug chemistry Inborn error of metabolism Disease Models Mutation 570 Life sciences biology Missense 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Genes, 11(9):1033, 1-20. Multidisciplinary Digital Publishing Institute (MDPI) Genes, vol 11, iss 9 Vernau, K M, Struys, E, Letko, A, Woolard, K D, Aguilar, M, Brown, E A, Cissell, D D, Dickinson, P J, Shelton, G D, Broome, M R, Gibson, K M, Pearl, P L, König, F, van Winkle, T J, O'Brien, D, Roos, B, Matiasek, K, Jagannathan, V, Drögemüller, C, Mansour, T A, Brown, C T & Bannasch, D L 2020, ' A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog ', Genes, vol. 11, no. 9, 1033, pp. 1-20 . https://doi.org/10.3390/genes11091033 Genes Volume 11 Issue 9 Genes, Vol 11, Iss 1033, p 1033 (2020) 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 |
| ISSN: | 2073-4425 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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