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

Histochemistry and electron microscopy of muscle fibers from SAN-affected (B, C and D) and control dogs (A).(A and B) Histochemistry showing the combined reaction for SDH and COX. Note the bluish reaction for the affected dog, indicating lack of COX activity. Bar = 200 µm. (C and D) Electron microscopy showing paracrystalline inclusions in a case. Bar = 0.5 µm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2683749&req=5

pgen-1000499-g004: Histochemistry and electron microscopy of muscle fibers from SAN-affected (B, C and D) and control dogs (A).(A and B) Histochemistry showing the combined reaction for SDH and COX. Note the bluish reaction for the affected dog, indicating lack of COX activity. Bar = 200 µm. (C and D) Electron microscopy showing paracrystalline inclusions in a case. Bar = 0.5 µm.

Mentions: Hematoxylin-eosin staining showed normal morphology for all examined biopsies. For the oxidative enzymes the reactions were more even and compact over the cut surface of the fibers for four of the affected dogs and in one control healthy dog (Table S1). In the combined reaction for succinate dehydrogenase (SDH) and cytochrome oxidase (COX) these also showed a bluish staining compared with the controls and affected dog nr. 3 (Figures 4A and B). Fibers showing total lack of cytochrome oxidase activity were not detected.


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)

Histochemistry and electron microscopy of muscle fibers from SAN-affected (B, C and D) and control dogs (A).(A and B) Histochemistry showing the combined reaction for SDH and COX. Note the bluish reaction for the affected dog, indicating lack of COX activity. Bar = 200 µm. (C and D) Electron microscopy showing paracrystalline inclusions in a case. Bar = 0.5 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000499-g004: Histochemistry and electron microscopy of muscle fibers from SAN-affected (B, C and D) and control dogs (A).(A and B) Histochemistry showing the combined reaction for SDH and COX. Note the bluish reaction for the affected dog, indicating lack of COX activity. Bar = 200 µm. (C and D) Electron microscopy showing paracrystalline inclusions in a case. Bar = 0.5 µm.
Mentions: Hematoxylin-eosin staining showed normal morphology for all examined biopsies. For the oxidative enzymes the reactions were more even and compact over the cut surface of the fibers for four of the affected dogs and in one control healthy dog (Table S1). In the combined reaction for succinate dehydrogenase (SDH) and cytochrome oxidase (COX) these also showed a bluish staining compared with the controls and affected dog nr. 3 (Figures 4A and B). Fibers showing total lack of cytochrome oxidase activity were not detected.

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