Abstract
Intronic DNA sequences of the canine arrestin (SAG ) gene was screened to identify potential disease causing mutations in dogs with generalized progressive retinal atrophy (gPRA). The intronic sequences flanking each of the 16 exons were obtained from clones of a canine genomic library. Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequence analyses we screened affected and unaffected dogs of 23 breeds with presumed autosomal recessively (ar) transmitted gPRA. In the coding region of the SAG gene 12 nucleotide exchanges were identified, 5 of which lead to amino acid substitutions (H14C; A111V; A113T; D259T; A379E). 7 other exonic substitutions represent silent polymorphisms (C132C; Q199Q; H225H; V247V; P264P; T288T and L293L). 16 additional sequence variations were observed in intronic regions of different dog breeds. In several breeds, these polymorphisms were found in homozygous state in unaffected and in heterozygous state in affected animals. Consequently these informative substitutions provide evidence to exclude mutations in the SAG gene as causing retinal degeneration in 14 of the 23 dog breeds with presumed ar transmitted gPRA.
Highlights
Intronic DNA sequences of the canine arrestin (SAG) gene was screened to identify potential disease causing mutations in dogs with generalized progressive retinal atrophy
None of the amino acid changes identified here in dogs correspond to residues that are mutated in known retinitis pigmentosa (RP), nor are they known to be important for binding activated dephosphorylated RHO [22,23,27]
These novel sequence variations can be used as intragenic markers for segregation analyses with ar generalized progressive retinal atrophy (gPRA)
Summary
Intronic DNA sequences of the canine arrestin (SAG) gene was screened to identify potential disease causing mutations in dogs with generalized progressive retinal atrophy (gPRA). GPRA is usually inherited as an ar blinding disorder with different ages of onset and variable rate of progression observed in more than 100 dog breeds. At least 4 genes were identified so far as causing gPRA in 6 breeds. All of these genes encode photoreceptor specific proteins involved in the visual transduction cascade including the β-subunit of the cGMP-specific phosphodiesterase (PDE6B) in Irish Setters and Sloughis [8,9] as well as the α-subunit of the cGMPspecific phosphodiesterase (PDE6A) in Cardigan Welsh Corgis [10].
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