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Sensory ataxic neuropathy in golden retriever dogs is caused by a deletion in the mitochondrial tRNATyr gene.

Baranowska I, Jäderlund KH, Nennesmo I, Holmqvist E, Heidrich N, Larsson NG, Andersson G, Wagner EG, Hedhammar A, Wibom R, Andersson L - PLoS Genet. (2009)

Bottom Line: Northern blot analysis showed that tRNA(Tyr) 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 tRNA(Tyr) gene is the causative mutation for SAN.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.

ABSTRACT
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 tRNA(Tyr) 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 tRNA(Tyr) 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 tRNA(Tyr) gene is the causative mutation for SAN.

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Related in: MedlinePlus

A schematic pedigree of golden retrievers affected by sensory ataxic neuropathy (SAN) and their relatives.In total we had access to blood samples from 20 out of 25 affected dogs (marked red or black) that can be traced back on the maternal side to female X. We also had access to samples from 13 first, second, third or fourth degree relatives of affected dogs (marked yellow). More distant relatives descendant of females Y or Z are marked with green. Only litters with affected dogs and sampled litters are included.
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pgen-1000499-g001: A schematic pedigree of golden retrievers affected by sensory ataxic neuropathy (SAN) and their relatives.In total we had access to blood samples from 20 out of 25 affected dogs (marked red or black) that can be traced back on the maternal side to female X. We also had access to samples from 13 first, second, third or fourth degree relatives of affected dogs (marked yellow). More distant relatives descendant of females Y or Z are marked with green. Only litters with affected dogs and sampled litters are included.

Mentions: Pedigree analysis of the 25 affected dogs revealed that they all belong to the same maternal lineage, and can be traced back to a female X that lived during the 1970s (Figure 1). In order to test if these data exclude a possible nuclear inheritance we calculated the prevalence of disease in offspring from all males and females in those litters where the mothers to the affected dogs were one of the siblings. If the risk factor was present in the nuclear genome, the proportion of affected progeny should be about the same from male and female parents in this maternal lineage. By contrast, all cases should derive from female parents if the risk factor is encoded in the mtDNA genome. We observed 25 affected dogs among 272 progeny from female dogs but no affected dogs among 177 progeny sired by males (P<10−6; Fisher's exact test). This provides conclusive evidence that SAN shows mitochondrial transmission.


Sensory ataxic neuropathy in golden retriever dogs is caused by a deletion in the mitochondrial tRNATyr gene.

Baranowska I, Jäderlund KH, Nennesmo I, Holmqvist E, Heidrich N, Larsson NG, Andersson G, Wagner EG, Hedhammar A, Wibom R, Andersson L - PLoS Genet. (2009)

A schematic pedigree of golden retrievers affected by sensory ataxic neuropathy (SAN) and their relatives.In total we had access to blood samples from 20 out of 25 affected dogs (marked red or black) that can be traced back on the maternal side to female X. We also had access to samples from 13 first, second, third or fourth degree relatives of affected dogs (marked yellow). More distant relatives descendant of females Y or Z are marked with green. Only litters with affected dogs and sampled litters are included.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2683749&req=5

pgen-1000499-g001: A schematic pedigree of golden retrievers affected by sensory ataxic neuropathy (SAN) and their relatives.In total we had access to blood samples from 20 out of 25 affected dogs (marked red or black) that can be traced back on the maternal side to female X. We also had access to samples from 13 first, second, third or fourth degree relatives of affected dogs (marked yellow). More distant relatives descendant of females Y or Z are marked with green. Only litters with affected dogs and sampled litters are included.
Mentions: Pedigree analysis of the 25 affected dogs revealed that they all belong to the same maternal lineage, and can be traced back to a female X that lived during the 1970s (Figure 1). In order to test if these data exclude a possible nuclear inheritance we calculated the prevalence of disease in offspring from all males and females in those litters where the mothers to the affected dogs were one of the siblings. If the risk factor was present in the nuclear genome, the proportion of affected progeny should be about the same from male and female parents in this maternal lineage. By contrast, all cases should derive from female parents if the risk factor is encoded in the mtDNA genome. We observed 25 affected dogs among 272 progeny from female dogs but no affected dogs among 177 progeny sired by males (P<10−6; Fisher's exact test). This provides conclusive evidence that SAN shows mitochondrial transmission.

Bottom Line: Northern blot analysis showed that tRNA(Tyr) 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 tRNA(Tyr) gene is the causative mutation for SAN.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.

ABSTRACT
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 tRNA(Tyr) 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 tRNA(Tyr) 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 tRNA(Tyr) gene is the causative mutation for SAN.

Show MeSH
Related in: MedlinePlus