title: L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model.
abstract: l-2-hydroxyglutaric aciduria (l-2-HGA) is a neurometabolic disorder that produces a variety of clinical neurological deficits, including psychomotor retardation, seizures and ataxia. The biochemical hallmark of l-2-HGA is the accumulation of l-2-hydroxyglutaric acid (l-2-HG) in cerebrospinal fluid, plasma and urine. Mutations within the gene L2HGDH (Entrez Gene ID 79944) on chromosome 14q22 encoding L-2-hydroxyglutaric acid dehydrogenase have recently been shown to cause l-2-HGA in humans. Using a candidate gene approach in an outbred pet dog population segregating l-2-HGA, the causal molecular defect was identified in the canine homologue of L2HGDH and characterised. DNA sequencing and pedigree analysis indicate a common founder effect in the canine model. The canine model shares many of the clinical and MRI features of the disease in humans and represents a valuable resource as a spontaneous model of l-2-HGA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Penderis
authors.forename: Jacqui
authors.initials: J
authors.lastname: Calvin
authors.forename: Carley
authors.initials: C
authors.lastname: Abramson
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Louise
authors.initials: L
authors.lastname: Pettitt
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Binns
authors.forename: Nanda M
authors.initials: NM
authors.lastname: Verhoeven
authors.forename: Eamonn
authors.initials: E
authors.lastname: O'Driscoll
authors.forename: Simon R
authors.initials: SR
authors.lastname: Platt
authors.forename: Cathryn S
authors.initials: CS
authors.lastname: Mellersh
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000662:veterinary*; D000595:Amino Acid Sequence; D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000000981:diagnostic imaging; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000201:enzymology / Q000235:genetics*; D004285:Dogs; D005091:Exons / Q000235:genetics; D005977:Glutarates / Q000378:metabolism* / Q000652:urine; D050770:Glutaryl-CoA Dehydrogenase / Q000737:chemistry / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D008279:Magnetic Resonance Imaging; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011859:Radiography
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D050770:Glutaryl-CoA Dehydrogenase