Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene
et al. (2009) Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a
Deletion in the Mitochondrial tRNATyr Gene. PLoS Genet 5(5): e1000499. doi:10.1371/journal.pgen.1000499
Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Tyr Caused by a Deletion in the Mitochondrial tRNA Gene
Izabella Baranowska 0
Karin Hultin Ja derlund 0
Inger Nennesmo 0
Erik Holmqvist 0
Nadja Heidrich 0
Nils-Go ran Larsson 0
Go ran Andersson 0
E. Gerhart H. Wagner 0
A ke Hedhammar 0
Rolf Wibom 0
Leif 0
Michel Georges, University of Lie`ge, Belgium
0 1 Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden, 2 Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden, 3 Department of Companion Animal Clinical Sciences, Norwegian School of Veterinary Science , Oslo , Norway , 4 Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden, 5 Department of Cell and Molecular Biology, Uppsala University , Uppsala , Sweden , 6 Department of Medical Biochemistry and Microbiology, Uppsala University , Uppsala , Sweden
Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNATyr gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0-11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNATyr had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNATyr gene is the causative mutation for SAN.
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Funding: This work was supported by grants from the Swedish Foundation for Strategic Research, The Swedish Research Council for Environment, Agricultural
Sciences, and Spatial Planning, Agria Insurance Company, Sweden, Funds of the Karolinska Institutet, the Golden Retriever Club of Sweden and the Swedish
Kennel Club.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Competing Interests: The authors have declared that no competing interests exist.
Sensory ataxic neuropathy (SAN) is a recently identified
neurological disorder in golden retrievers [1]. SAN has an
insidious onset during puppyhood, followed by slow progression.
Males and females are affected at similar frequencies. Affected
dogs are ataxic, have postural reaction deficits and reduced or
absent spinal reflexes. They have no pronounced muscle atrophy,
and the dogs do not seem to be in pain. Electrophysiological
examination revealed that they have reduced conduction velocities
of nerve impulses in sensory nerves. Pathological examination
indicated degenerative changes both in the central and peripheral
nervous system. Approximately fifty percent of the affected dogs
were euthanized before three years of age. A preliminary
examination of pedigree data showed that all affected dogs could
be traced back to a female on the maternal side that lived in the
1970s, suggesting that SAN could be caused by a mutation in the
mitochondrial genome (mtDNA).
Mitochondrial disorders, caused by mutations in maternally
inherited mtDNA, are a group of heterogeneous diseases in
humans. More than 250 pathogenic point mutations as well as
small and large scale rearrangements of mtDNA have been
identified [2], and with an estimated incidence of approximately 1
in 8000 in the Caucasian population, mitochondrial disorders are
considered to be among the most common forms of metabolic
disease [3]. They usually manifest in energy-consuming tissues
such as the central nervous system, muscles, auditory system and
visual system, but almost any organ in any combination might be
involved and age at onset often varies widely.
The genotype/phenotype relationship for mtDNA mutation
diseases is only partly understood. A somatic mammalian cell
typically contains thousands of mtD (...truncated)