Limits...
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.

Show MeSH

Related in: MedlinePlus

Characterization of the ΔT5304 deletion in the tRNATyr gene.(A) The mutation deleted the A of the innermost base pair of the TΨC stem, as indicated in the cloverleaf structure of tRNATyr. (B) A quantitative oligonucleotide ligation assay (qOLA) was used to estimate the relation between wild-type and mutant molecules in blood samples from golden retrievers. W represents 71 unrelated golden retriever dogs that all show 100% wt molecules. The green bars represent the degree of heteroplasmy of distant relatives (34.8 (22.0); mean (SD)), yellow bars stand for close relatives (5.1 (2.8)) and the red bars represent affected dogs (4.9 (3.5)). (C) Northern blot analyses using probes for mt tRNATyr, mt tRNACys and mt tRNAGln and RNA from three SAN-affected golden retrievers and two unaffected dogs; one dachshund (Control 1) and one golden retriever (Control 2). The values given at the bottom of the blots for mt tRNATyr and mt tRNACys is the relative hybridization intensity normalized using the hybridization intensity for mt tRNAGln. The sample with the highest normalized hybridization intensity was given the value 1.00.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2683749&req=5

pgen-1000499-g002: Characterization of the ΔT5304 deletion in the tRNATyr gene.(A) The mutation deleted the A of the innermost base pair of the TΨC stem, as indicated in the cloverleaf structure of tRNATyr. (B) A quantitative oligonucleotide ligation assay (qOLA) was used to estimate the relation between wild-type and mutant molecules in blood samples from golden retrievers. W represents 71 unrelated golden retriever dogs that all show 100% wt molecules. The green bars represent the degree of heteroplasmy of distant relatives (34.8 (22.0); mean (SD)), yellow bars stand for close relatives (5.1 (2.8)) and the red bars represent affected dogs (4.9 (3.5)). (C) Northern blot analyses using probes for mt tRNATyr, mt tRNACys and mt tRNAGln and RNA from three SAN-affected golden retrievers and two unaffected dogs; one dachshund (Control 1) and one golden retriever (Control 2). The values given at the bottom of the blots for mt tRNATyr and mt tRNACys is the relative hybridization intensity normalized using the hybridization intensity for mt tRNAGln. The sample with the highest normalized hybridization intensity was given the value 1.00.

Mentions: We re-sequenced the complete mitochondrial genome of seven dogs: four affected golden retrievers (GRs), one close relative and two unrelated GRs. A one base pair deletion was identified at position 5304 in tRNATyr of the affected dogs and their relatives (Figure 2A). This was the only sequence variant that was uniquely associated with the disease. This variant has not been found in any other dog breed and this position in mtDNA is highly conserved among vertebrates.


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)

Characterization of the ΔT5304 deletion in the tRNATyr gene.(A) The mutation deleted the A of the innermost base pair of the TΨC stem, as indicated in the cloverleaf structure of tRNATyr. (B) A quantitative oligonucleotide ligation assay (qOLA) was used to estimate the relation between wild-type and mutant molecules in blood samples from golden retrievers. W represents 71 unrelated golden retriever dogs that all show 100% wt molecules. The green bars represent the degree of heteroplasmy of distant relatives (34.8 (22.0); mean (SD)), yellow bars stand for close relatives (5.1 (2.8)) and the red bars represent affected dogs (4.9 (3.5)). (C) Northern blot analyses using probes for mt tRNATyr, mt tRNACys and mt tRNAGln and RNA from three SAN-affected golden retrievers and two unaffected dogs; one dachshund (Control 1) and one golden retriever (Control 2). The values given at the bottom of the blots for mt tRNATyr and mt tRNACys is the relative hybridization intensity normalized using the hybridization intensity for mt tRNAGln. The sample with the highest normalized hybridization intensity was given the value 1.00.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000499-g002: Characterization of the ΔT5304 deletion in the tRNATyr gene.(A) The mutation deleted the A of the innermost base pair of the TΨC stem, as indicated in the cloverleaf structure of tRNATyr. (B) A quantitative oligonucleotide ligation assay (qOLA) was used to estimate the relation between wild-type and mutant molecules in blood samples from golden retrievers. W represents 71 unrelated golden retriever dogs that all show 100% wt molecules. The green bars represent the degree of heteroplasmy of distant relatives (34.8 (22.0); mean (SD)), yellow bars stand for close relatives (5.1 (2.8)) and the red bars represent affected dogs (4.9 (3.5)). (C) Northern blot analyses using probes for mt tRNATyr, mt tRNACys and mt tRNAGln and RNA from three SAN-affected golden retrievers and two unaffected dogs; one dachshund (Control 1) and one golden retriever (Control 2). The values given at the bottom of the blots for mt tRNATyr and mt tRNACys is the relative hybridization intensity normalized using the hybridization intensity for mt tRNAGln. The sample with the highest normalized hybridization intensity was given the value 1.00.
Mentions: We re-sequenced the complete mitochondrial genome of seven dogs: four affected golden retrievers (GRs), one close relative and two unrelated GRs. A one base pair deletion was identified at position 5304 in tRNATyr of the affected dogs and their relatives (Figure 2A). This was the only sequence variant that was uniquely associated with the disease. This variant has not been found in any other dog breed and this position in mtDNA is highly conserved among vertebrates.

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