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Molecular genetic investigations of rod cyclic GMP phosphodiesterase beta subunit in canine generalised progressive retinal atrophy

Clements, Peter James Mackenzie; (1995) Molecular genetic investigations of rod cyclic GMP phosphodiesterase beta subunit in canine generalised progressive retinal atrophy. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Generalised Progressive Retinal Atrophy (GPRA) is a collective term describing a number of phenotypically and genotypically heterogeneous, autosomal recessive retinal dystrophies and degenerations segregating in specific breeds of dog. All result in blindness and collectively, show much similarity to Retinitis Pigmentosa, a group of important human inherited retinal degenerations. GPRA in the Irish setter is given the locus designation rcd-1 (Rod-Cone Dysplasia Type 1) and presents as an early onset photoreceptor dystrophy with rapid, progressive loss of cells complete by approximately one year. Biochemically, the earliest detected abnormality is an accumulation of retinal cGMP, due to a defective phosphodiesterase activity. Therefore, the possibility that a mutation in the rod cGMP phosphodiesterase beta subunit (pdeb) gene causes rcd-1 in Irish setters was investigated. The normal canine pdeb cDNA, was cloned and sequenced, spanning the entire coding region to the poly-A tail. Additionally, partial intron/exon characterisation and nucleotide substitution analysis was undertaken to investigate the relationship of canine pdeb to its homologue in other species and to other members of the photoreceptor PDE family. A recently reported G to A transition in the pdeb gene described in rcd-1 setters in the USA was confirmed in affected dogs in the UK. In addition, GPRA in two other breeds, miniature longhaired dachshunds and Tibetan terriers was shown not to be due to this mutation, which creates a premature stop codon at residue 807. A rapid, non-isotopic diagnostic test was developed and used to show cosegregation of the mutation with rcd-1 phenotype in an Irish setter pedigree. Anchored PCR has been utilised to generate upstream sequence information from genomic DNA, and in tandem with mapping of the 5' end of the transcript has revealed sequence motifs in the proximal promoter of the canine pdeb gene which are conserved with the human gene. The tissue distribution of pdeb transcripts was investigated by Reverse Transcriptase-PCR and Northern analysis and the results show that transcription is not confined to the retina, but can be detected in a variety of different tissues.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Molecular genetic investigations of rod cyclic GMP phosphodiesterase beta subunit in canine generalised progressive retinal atrophy
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10097674
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