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BMC Vet Res. 2012; 8: 124.
Published online Jul 26, 2012. doi:  10.1186/1746-6148-8-124
PMCID: PMC3461439
A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2-hydroxyglutaric aciduria
Fabiana HG Farias,corresponding author1 Rong Zeng,1 Gary S Johnson,1 G D Shelton,2 Dominique Paquette,3 and Dennis P O’Brien4
1Department of Veterinary Pathobiology, University of Missouri, Columbia, USA
2Department of Pathology, University of California at San Diego, La Jolla, USA
3Centre Veterinaire DMV, Montreal, Canada
4Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, USA
corresponding authorCorresponding author.
Fabiana HG Farias: fhfdpd/at/mail.missouri.edu; Rong Zeng: rz32f/at/mail.missouri.edu; Gary S Johnson: johnsongs/at/missouri.edu; G D Shelton: gshelton/at/ucsd.edu; Dominique Paquette: dpaquette/at/centredmv.com; Dennis P O’Brien: obriend/at/missouri.edu
Received April 9, 2012; Accepted July 4, 2012.
Abstract
Background
L-2-hydroxyglutaric aciduria is a metabolic repair deficiency characterized by elevated levels of L-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid. Neurological signs associated with the disease in humans and dogs include seizures, ataxia and dementia.
Case presentation
Here we describe an 8 month old Yorkshire terrier that presented with episodes of hyperactivity and aggressive behavior. Between episodes, the dog’s behavior and neurologic examinations were normal. A T2 weighted MRI of the brain showed diffuse grey matter hyperintensity and a urine metabolite screen showed elevated 2-hydroxyglutaric acid. We sequenced all 10 exons and intron-exon borders of L2HGDH from the affected dog and identified a homozygous A to G transition in the initiator methionine codon. The first inframe methionine is at p.M183 which is past the mitochondrial targeting domain of the protein. Initiation of translation at p.M183 would encode an N-terminal truncated protein unlikely to be functional.
Conclusions
We have identified a mutation in the initiation codon of L2HGDH that is likely to result in a non-functional gene. The Yorkshire terrier could serve as an animal model to understand the pathogenesis of L-2-hydroxyglutaric aciduria and to evaluate potential therapies.
Keywords: L-2-hydroxyglutaric aciduria, L2HGDH, Yorkshire terrier, Initiator methionine codon
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