A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever.
Alexander disease (AxD) is a fatal neurodegenerative disorder of astrocyte dysfunction in man, for which already a number of causal variants are described, mostly de novo dominant missense variants in the glial fibrillary acidic protein (GFAP). A similar disorder was already phenotypically described in animals but without the identification of causal variants. We diagnosed a Labrador retriever with a juvenile form of AxD based on clinical (tetraparesis with spastic front limbs mimicking 'swimming puppy syndrome') and pathological (the detection of GFAP containing Rosenthal fibers in astrocytes) features. In order to identify a causal variant, the coding sequences of the four detected GFAP transcript variants (orthologues from human transcript variants α, γ, δ/ɛ and κ) were sequenced. From the five detected variants, a heterozygous c.719G>A nucleotide substitution resulting in a p.Arg240His substitution was considered to be causal, because it is orthologous to the heterozygous de novo dominant c.716G>A (p.Arg239His) hotspot variant in man, proven to cause a severe phenotype. In addition, the variant was not found in 50 unrelated healthy Labrador retrievers. Because the condition in dogs is morphologically similar to man, it could be a promising animal model for further elucidating the genotype/phenotype correlation in order to treat or prevent this disease.
Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Mario
M
Van Poucke
Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Valentine
V
Martlé
Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Leen
L
Van Brantegem
Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Richard
R
Ducatelle
Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Luc
L
Van Ham
Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Sofie
S
Bhatti
Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Luc J
LJ
Peelman
D038261:Alexander Disease / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D000818:Animals; D004285:Dogs; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype
D005904:Glial Fibrillary Acidic Protein