Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene

PLoS Genetics, May 2009

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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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. - 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)


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Izabella Baranowska, Karin Hultin Jäderlund, Inger Nennesmo, Erik Holmqvist, Nadja Heidrich, Nils-Göran Larsson, Göran Andersson, E. Gerhart H. Wagner, Åke Hedhammar, Rolf Wibom, Leif Andersson. Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene, PLoS Genetics, 2009, Volume 5, Issue 5, DOI: 10.1371/journal.pgen.1000499