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Article

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

1
Department of Surgical and Radiological Sciences, University of California Davis, Davis, CA 95616, USA
2
Department of Clinical Chemistry, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
3
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland
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Department of Pathology, Microbiology and Immunology, University of California Davis, Davis, CA 95616, USA
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Department of Population Health and Reproduction, University of California Davis, Davis, CA 95616, USA
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Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA
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Advanced Veterinary Medical Imaging, Tustin, CA 92780, USA
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College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
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Harvard Medical School, Boston, MA 02115, USA
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Fachtierarzt fur Kleintiere, Am Berggewann 13, 65199 Wiesbaden, Germany
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Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
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Clinical and Comparative Neuropathology, Ludwig-Maximilians-Universitaet München, 80539 Munchen, Germany
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Department of Clinical Pathology, School of Medicine, Mansoura University, Mansoura 35516, Egypt
*
Authors to whom correspondence should be addressed.
Genes 2020, 11(9), 1033; https://doi.org/10.3390/genes11091033
Received: 7 August 2020 / Revised: 25 August 2020 / Accepted: 27 August 2020 / Published: 2 September 2020
(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)
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. View Full-Text
Keywords: inborn error of metabolism; encephalopathy; SSADHD; ALDH5A1; GABA; 4-hydroxybutyric acid; succinic semialdehyde; encephalopathy; whole-genome sequencing; precision medicine; GWAS; inherited inborn error of metabolism; encephalopathy; SSADHD; ALDH5A1; GABA; 4-hydroxybutyric acid; succinic semialdehyde; encephalopathy; whole-genome sequencing; precision medicine; GWAS; inherited
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MDPI and ACS Style

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. A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog. Genes 2020, 11, 1033. https://doi.org/10.3390/genes11091033

AMA Style

Vernau KM, Struys E, Letko A, Woolard KD, Aguilar M, Brown EA, Cissell DD, Dickinson PJ, Shelton GD, Broome MR, Gibson KM, Pearl PL, König F, Van Winkle TJ, O’Brien D, Roos B, Matiasek K, Jagannathan V, Drögemüller C, Mansour TA, Brown CT, Bannasch DL. A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog. Genes. 2020; 11(9):1033. https://doi.org/10.3390/genes11091033

Chicago/Turabian Style

Vernau, Karen M., Eduard Struys, Anna Letko, Kevin D. Woolard, Miriam Aguilar, Emily A. Brown, Derek D. Cissell, Peter J. Dickinson, G. D. Shelton, Michael R. Broome, K. M. Gibson, Phillip L. Pearl, Florian König, Thomas J. Van Winkle, Dennis O’Brien, B. Roos, Kaspar Matiasek, Vidhya Jagannathan, Cord Drögemüller, Tamer A. Mansour, C. T. Brown, and Danika L. Bannasch 2020. "A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog" Genes 11, no. 9: 1033. https://doi.org/10.3390/genes11091033

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