Genetic Mapping & Evaluation for Inborn Errors of Metabolism of a Primary Cerebellar Granule Cell Degeneration in the Jack Russell Terrier

Recipient Organization
UNIVERSITY OF MISSOURI
(N/A)
COLUMBIA,MO 65211

Performing Department
VETERINARY MEDICINE & SURGERY

Non Technical Summary
We discovered a cerebellar ataxia in Jack Russell Terrier dogs. The degenerative process causes loss of granule cells in the cerebellum. The cerebellum controls coordination of body movements. Affected dogs show progressive loss of coordination in all legs and other signs of cerebellar disease. The disease is suspected to be autosomal recessive. We propose an underlying genetic defect affects oxidative metabolism of granule cells. The goal of the proposed project is to reduce the prevalence of PCGD in the Jack Russell Terrier dog. We will try identifying a candidate gene for mapping to identify the chromosomal region containing the mutation and sequence the gene responsible for the PCGD.

Animal Health Component

50%

Research Effort Categories

Basic

(N/A)

Applied

50%

Developmental

50%

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
303	3830	1000	12%
303	3830	1040	13%
303	3830	1080	50%
304	3830	1060	25%

Knowledge Area
303 - Genetic Improvement of Animals; 304 - Animal Genome;

Subject Of Investigation
3830 - Pets (companion animals);

Field Of Science
1040 - Molecular biology; 1060 - Biology (whole systems); 1000 - Biochemistry and biophysics; 1080 - Genetics;

Goals / Objectives
We propose to apply a variety of molecular genetic and biochemical strategies to identify the mutation responsible for primary cerebellar granule cell degeneration (PCGD) in Jack Russell Terrier dogs. Complete organic and amino acid analyses on CSF will be performed to further document a defect in oxidative metabolism or other intermediary pathways. A candidate gene approach will be used initially to demonstrate linkage to specific markers for the PCGD phenotype. If we are able to link a candidate gene to the PCGD phenotype, we will determine its genomic sequence and causative mutation. If we are unable to demonstrate linkage to any of the candidate gene markers, the JRT DNA will be genotyped with a panel of microsatellite markers. We will focus on the whole-genome mapping studies which we expect to reveal the chromosomal region containing the mutation responsible for PCGD. If no candidates are found, we will devise new microsatellite markers from the canine candidate region for fine mapping to narrow the candidate region and identify a manageable number of genes for sequencing.

Project Methods
We propose to apply a variety of molecular genetic and biochemical strategies to identify the mutation responsible for primary cerebellar granule cell degeneration (PCGD) in Jack Russell Terrier dogs. Complete organic and amino acid analyses on CSF will be performed to further document a defect in oxidative metabolism or other intermediary pathways. A candidate gene approach will be used initially to demonstrate linkage to specific markers for the PCGD phenotype. If we are able to link a candidate gene to the PCGD phenotype, we will determine its genomic sequence and causative mutation. If we are unable to demonstrate linkage to any of the candidate gene markers, the JRT DNA will be genotyped with a panel of microsatellite markers. We will focus on the whole-genome mapping studies which we expect to reveal the chromosomal region containing the mutation responsible for PCGD. If no candidates are found, we will devise new microsatellite markers from the canine candidate region for fine mapping to narrow the candidate region and identify a manageable number of genes for sequencing.

Progress 03/01/05 to 12/31/06

Outputs
Cerebrospinal fluid (CSF) from six dogs with histopathologic confirmation of PCGD were selected for organic and amino acid quantification. Lactate was elevated in the CSF of 2 dogs. The lactate/pyruvate and acetoacetate/3OH butyrate ratios were not significantly different from those of normal control dogs. Amino acid quantification performed in 4 of 6 dogs failed to show significant alterations in amino acid concentrations. These results do not support a metabolic encephalopathy associated with early degeneration of cerebellar granule cells.

Impacts
The compilation of a strong pedigree map and clear phenotype should facilitate use of the SNP-chip for mapping PCGD in the Jack Russell Terrier and find the causative mutation.

Publications

No publications reported this period

Progress 01/01/05 to 12/31/05

Outputs
Projected extended, termination report will be submitted at project end.

Impacts
To be included at project end.

Publications

No publications reported this period