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Simon M. Petersen–Jones, David D. Entz, David R. Sargan; cGMP Phosphodiesterase-α Mutation Causes Progressive Retinal Atrophy in the Cardigan Welsh Corgi Dog. Invest. Ophthalmol. Vis. Sci. 1999;40(8):1637-1644.
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purpose. To screen the α-subunit of cyclic guanosine monophosphate (cGMP)
phosphodiesterase (PDE6A) as a potential candidate gene for
progressive retinal atrophy (PRA) in the Cardigan Welsh corgi dog.
methods. Single-strand conformation polymorphism (SSCP) analysis was used to
screen short introns of the canine PDE6A gene for
informative polymorphisms in members of an extended pedigree of
PRA-affected Cardigan Welsh corgis. After initial demonstration of
linkage of a polymorphism in the PDE6A gene with the
disease locus, the complete coding region of the PDE6A gene of a PRA-affected Cardigan Welsh corgi was cloned in overlapping
fragments and sequenced. SSCP-based and direct DNA sequencing tests
were developed to detect the presence of a PDE6A gene
mutation that segregated with disease status in the extended pedigree
of PRA-affected Cardigan Welsh corgis. Genomic DNA sequencing was
developed as a diagnostic test to establish the genotype of Cardigan
Welsh corgis in the pet population.
results. A polymorphism within intron 18 of the canine PDE6A gene
was invariably present in the homozygous state in PRA-affected Cardigan
Welsh corgis. The entire PDE6A gene was cloned from one
PRA-affected dog and the gene structure and intron sizes established
and compared with those of an unaffected animal. Intron sizes were
identical in affected and normal dogs. Sequencing of exons and splice
junctions in the affected animal revealed a 1-bp deletion in codon 616.
Analysis of PRA-affected and obligate carrier Cardigan Welsh corgis
showed that this mutation cosegregated with disease status.
conclusions. A single base deletion at codon 616 in the PDE6A gene
cosegregated with PRA status with zero discordance in Cardigan Welsh
corgis with PRA. A lod score of 4.816 with a recombination fraction
(θ) of zero strongly suggests that this mutation is responsible for
PRA in the breed. The mutation is predicted to lead to a frame shift
resulting in a string of 28 altered codons followed by a premature stop
codon. The authors suggest that this type of PRA be given the name
rod–cone dysplasia 3 (rcd3).
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