Wilkie SE, Newbold RJ, Deery E et al 2000 Functional characterisation of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone-rod dystrophy. Hum Mol Genet 9:3065^3073

Wilkie SE, Li Y, Deery EC et al 2001 Identi¢cation and functional consequences of a new mutation (E155G) in GCAP1 causing autosomal dominant cone dystrophy. Am J Hum Genet 69:471^480

Yang RB, Robinson SW, Xiong WH, Yau KW, Birch DG, Garbers DL 1999 Disruption of a retinal guanylyl cyclase gene leads to cone-speci¢c dystrophy and paradoxical rod behavior. J Neurosci 19:5889^5897

DISCUSSION

Baehr: There are three GCAPs in the human retina. Did you screen all the individuals of families for GCAP2 and GCAP3 mutations?

Hunt: No.

Molday: The knockout mouse for retCG1 shows primarily a cone degeneration phenotype. What is the state of the rod cells in relation to the presence and location of retCG1 and retCG2?

Hunt: The knockout phenotype would indeed seem to ¢t with the fact that the cones seem to be more sensitive than the rods to loss of retGC1. Bear in mind however that a knockout null mutation of retGC1 is not equivalent to the dominant mutations that we have studied.

Baehr: Yang et al (1999) said that the rod response is abnormal but it is there in the retGC1 knockout. This means that there must be another cyclase in rods in the absence of retGC1. It is a mystery.

Zack: In terms of expression patterns as well as clinical phenotype, are there di¡erences between di¡erent cone subtypes?

Hunt: I’m not sure.

Bird: I can’t remember, but the photophobia that they have is really quite exceptional. Members in the initial family ¢nd even threshold stimuli to be unpleasant. Hence it was very di⁄cult to characterize the disorder. The arginine/cysteine mutation is much milder, and as children the patients carrying this couldn’t see in bright light. However, at the age of 40 years they still had good acuity. They had this strange symptom that in bright light they couldn’t see, yet they maintained quite good cone function under mesopic conditions for years.

Zack: In terms of gene expression or in the knockout, are there di¡erences between di¡erent wavelength cones?

Hunt: As far as I know this hasn’t been looked at. I don’t think there is any evidence for the di¡erential expression of retGC isoforms in the di¡erent cone classes.

Aguirre: One of the questions you raised, which I think is important to resolve, is what is really causing the cells to become sick and die? cGMP is rising, but this might not be what is killing the cells. It may be a¡ecting transduction. The Ca2+ seems a more promising possibility, and one that might be more easily addressable for treatment using Ca2+ channel blockers. Several years ago we did a study in which we crossed mouse strains with di¡erent mutations, including rd and rds. The rd retinas lost photoreceptors very quickly and had a very high level of cGMP. The rds mutants lost them slowly and had lower than normal levels of cGMP. The double homozygotes had as high a level as the rd mutants, but lost photoreceptors at an intermediate rate. These cells are also abnormal in that they don’t have an outer segment. This may be a compartmentalization issue as the double rd/rds homozygotes lacked an outer segment.

Farber: How high were the levels of cGMP? Did you measure them?

Aguirre: The levels were measured and in both the rd and rd/rds double homozygotes the peak levels of cGMP were approximately 10-fold higher than normal controls.

Hunt: This is where the animal models come in. They will be particularly valuable in determining changes in cGMP and Ca2+ levels arising as a result of these mutations.

Reference

Yang RB, Robinson SW, Xiong WH, Yau KW, Birch DG, Garbers DL 1999 Disruption of a retinal guanylyl cyclase gene leads to cone-speci¢c dystrophy and paradoxical rod behavior. J Neurosci 19:5889^5897