Low docosahexaenoic acid levels in rod outer segment membranes of mice with rds/peripherin and P216L peripherin mutations

Humans with retinitis pigmentosa and dogs with progressive rod-cone degener ation (prcd) have lower than normal blood levels of long-chain prcd-unsatur ated fatty acids, including docosahexaenoic acid (DHA), the major fatty aci d found in retinal rod outer segments (ROS). In addition, prcd-affected dog s have lower levels of DHA in their ROS than control animals. The present s tudy was designed to determine whether mice that are heterozygous for the m s mutation and transgenic mice heterozygous for a specific rds/peripherin m utation (P216L) have lower DHA levels in their ROS and other tissues than d o control mice. METHODS. Wild-type (rds(+/+)) mice, mice with the rds(-/-) (null) and rds(/-) mutations, and mice with the P216L rds/peripherin mutation on the rds(/-) background were maintained in the vivarium under identical husbandry co nditions, and tissues were removed from each group for analysis at approxim ately 2 months of age. Fatty acid compositions of total lipids from plasma, red blood cells, liver, and ROS were determined by gas-liquid chromatograp hy. ROS purity. from each group was determined by SDS-PAGE with silver stai ning. The morphologic status of retinas representing each genotype was anal yzed by light and electron microscopy. RESULTS. There was no difference between rds(+/-), P216L on rds(+/-), and r ds(+/+) (control) animals in the fatty acid composition of plasma, expresse d as relative mole percent or as nanomoles fatty acid per milliliter of pla sma. Small but statistically significant differences were found in 18:0 and C-22 poly unsaturated fatty acids of red blood cells. In the liver, the co ntrol animals had higher levels of 20:4n-6. In contrast, the ROS of control animals had levels of DHA that were 1.4 times that of ROS from either rds( +/-) or P216L on rds(+/-) mice of the same age. The reduction in DHA was no t accompanied by an increase in 22:5n-6, which always occurs in neural tiss ues of animals deprived of n-3 fatty acids. SDS-PAGE of the three ROS membr ane preparations showed that they were of identical purity. CONCLUSIONS. Mice heterozygous for the spontaneous rds/peripherin mutation or mice carrying the P216L mutation on this heterozygous background have a statistically significant reduction of DHA in their ROS membranes. The auth ors propose that reduction in DHA is an adaptive response to metabolic stre ss caused by the mutation.