Rpe65 Variants Affect Vision in Animal Models

Vision researchers are very familiar with several mutations which can affect sight in mice. Chang et al. cataloged 16 separate mutations causing retinal degeneration. Two of the better known mutations are Pde6b^rd1 (commonly called rd1) and Crb1^rd8 (commonly called rd8). The rd1 mutation is present in a number of inbred strains, such as FVB and SJL, and causes blindness by weaning age. The rd8 mutation is present in C57BL/6N sublines, including C57BL/6NTac, and causes a slow retinal degeneration.

Savvy scientists select inbred strains and GEMs on particular genetic backgrounds to avoid confounding vision mutations for experiments where sight is relevant¹.

There are additional sight-affecting mutations which may not be as well known, but which can have confounding effects in certain studies. Mutations in Rpe65, in particular, contribute to light-induced photoreceptor damage, but are often overlooked during the model selection process.

How Can Rpe65 Mutations Affect Vision?

The Rpe65 gene produces an enzyme expressed in the retinal pigment epithelium (RPE). RPE65 is involved in the regeneration of functional visual pigment (rhodopsin). Mutations in Rpe65 are associated with a number of human diseases, including autosomal recessive retinitis pigmentosa². A naturally occurring mutant in Rpe65 called rd12 (Rpe65^rd12) was discovered in a colony of B6.A-H2-T18^a/BoyEg mice; this mutation causes functional deficiencies as measured by rod electroretinography³.

The Rpe65^rd12 mutation is not widespread, but at least two naturally occurring alleles of Rpe65 have been characterized in inbred strains which may impact vision. Prolonged light exposure can cause damage to mouse photoreceptors, particularly in albino animals; the Rpe65^450M allele (found in the C57BL/6J and C57BL/6J-Tyr^c-2J strains) was found to be protective against this damage, and the Rpe65^450L allele (found in the BALB/cByJ and 129X1/SvJ strains) was not, resulting in loss of photoreceptor cells. The proteins expressed from the Rpe65^450M and Rpe65^450L alleles produce different kinetics for rhodopsin regeneration^4-7.

Which Animal Model Strains Carry Rpe65 Variants?

Little work has been done to characterize which allele is present in other inbred strains, but vision researchers should be aware of this difference if they compare C57BL/6 mice to BALB/c or 129 mice. Researchers using mice on mixed backgrounds consisting of C57BL/6 and BALB/c or C57BL/6 and 129 should be aware of the possibility that both alleles may be segregating in the population. Individual mice could be any one of the following genotypes in such a situation:

If Rpe65 allele status is critical to an experiment, use of a single inbred strain or a GEM which has been either generated directly on an inbred background or sufficiently backcrossed to an inbred background may be required. Because the Rpe65 allelic status of many common inbred strains has not been validated, caution is advised when using GEMs on mixed backgrounds for experiments where Rpe65 allele status may affect the outcome.

References:

1. Chang, B.; Hawes, N.; Hurd, R.; Davisson, M.; Nusinowitz, S.; Heckenlively, J. Vision Research 2002, 42 (4), 517-525.

2. Cai, X.; Conley, S. M.; Naash, M. I. Ophthalmic Genetics 2009, 30 (2), 57-62.

3. Pang, J.J.; Chang, B.; Hawes, N.L.; Hurd, R.E.; Davisson, M.T.; Li J.; Noorwez, S.M.; Malhotra, R.; McDowell, J.H.; Kaushal, S.; Hauswirth, W.W.; Nusinowitz, S.; Thompson, D.A.; Heckenlively, J.R. Mol Vis. 2005 11, 152-62.

4. Danciger, M.; Matthes, M. T.; Yasamura, D.; Akhmedov, N. B.; Rickabaugh, T.; Gentleman, S.; Redmond, T. M.; Vail, M. M. L.; Farber, D. B. Mammalian Genome 2000, 11 (6), 422-427.

5. Nusinowitz, S.; Nguyen, L.; Radu, R.; Kashani, Z.; Farber, D.; Danciger, M. Experimental Eye Research 2003, 77 (5), 627-638.

6. Wenzel, A.; Remé, C. E.; Williams, T. P.; Hafezi, F.; Grimm, C. The Journal of Neuroscience 2001, 21 (1), 53-58.

7. Samardzija, M.; Wenzel, A.; Naash, M.; Remé, C. E.; Grimm, C. European Journal of Neuroscience 2006, 23 (4), 1028-1034.