Confirmation of the rod cGMP phosphodiesterase β subunit (PDEβ) nonsense mutation in affected rcd-1 Irish setters in the UK and development of a diagnostic test

Abstract

Rod/cone dysplasia type one (rcd-1) is an early onset inherited retinal dystrophy segregating in the Irish setter breed. It is classed as one of the autosomal recessive canine generalised Progressive Retinal Atrophies (PRA). The disease results in complete loss of photoreceptors by approximately one year of age. Levels of retinal cGMP are markedly elevated and of abnormal distribution in rod photoreceptors. Rod phosphodiesterase activity is absent and mRNA encoding the beta subunit (PDE beta) of the holoenzyme is uniquely reduced in predegenerate retinae. Using retinae from normal, unrelated adult dogs we have PCR-amplified and sequenced the cDNA for PDE beta. The cDNA is almost identical to that recently described for the Irish setter in the USA apart from two translationally silent single nucleotide changes. Using carrier and affected setters from a UK breeding colony we have screened genomic DNA and can confirm the G to A transition in rcd-1 affected dogs at position 2420, creating an amber mutation in codon 807. However, PRA-affected Tibetan terriers and miniature longhaired dachshunds are normal at this locus, underlining the genetic heterogeneity of this disease group. In addition we have developed a rapid, PCR-based diagnostic test for this mutation that will differentiate normal dogs from asymptomatic carriers.

Identification of Genetic Variants in <I>PDC, RHO, PDE6A</I> and <I>PDE6B</I> in Dogs with Progressive Retinal Atrophy

“…A different mutation in PDE6B for rcd1a was found to be associated with PRA in the Sloughi by using a candidate gene approach 22 . A stop mutation in exon 21 of canine PDE6B gene was also identified by sequencing in Iris Setters breed 21,40,41 . However, these mutations were not detected in our studied breeds.…”

“…Mutations in the PDE6A and PDE6B cause retinitis pigmentosa (OMIM: 268000) in human [35][36][37] . Mutations in PDE6B also cause retinal degeneration in the rd mouse 38,39 and the rcd1 dog 21,40,41 . A single base deletion at codon 616 in the PDE6A gene is co-segregated with PRA status with zero discordance in PRA affected Cardigan Welsh Corgis 23 .…”

Advances in the molecular understanding of canine retinal diseases

“…Thus the gene encoding the beta subunit of cyclic GMP phosphodiesterase (PDE6B) was a primary candidate for the site of the rcd1 mutation. Gene sequencing subsequently identified the causal mutation (Clements andothers 1993, Suber andothers 1993).…”

Incidence of the gene mutation causal for rod‐cone dysplasia type 1 in Irish setters in the UK

“…Analysis of known rcdl affected and carrier dogs and normal dogs of other breeds showed the mutation to co-segregate with disease status (Clements andothers 1993, Ray andothers 1994). Ray and others (1994) tested 58 dogs of known genotype, representing several generations of informative breeding from an rcdl colony, and 36 Irish setters from the general pet population in the USA which were suffering from gPRA.…”