Molecular and cellular impact of a C203R/C198R M-opsin mutation

A C203R mutation in M-opsin is a cause of blue cone monochromacy (BCM) in human patients. The equivalent mutation in murine M-opsin is C198R since human M-opsin has an extra 5 amino acid residues in the amino terminal region that are not present in murine M-opsin. The mechanism by which the C203R/C198R mutation causes BCM is unclear, and the function and dysfunction of cone opsins in general are understudied compared to that of rhodopsin in rod photoreceptor cells. To better understand the dysfunction caused by a C203R/C198R mutation in M-opsin, the effect of the mutation was examined both in vitro and in vivo. In in vitro studies, the mutant M-opsin on either human or murine backgrounds aggregated and was mislocalized in HEK293 cells. Although these in vitro properties of the mutant M-opsin were similar to those of misfolding rhodopsin mutants that cause autosomal dominant retinitis pigmentosa, the in vivo effects were comparatively less severe. The in vivo effect of the C198R mutation was characterized in knockin mice expressing the C198R M-opsin mutant. The mutation diminished the expression of M-opsin with some apparent mislocalization of the cone opsin without aggregation, which resulted in the loss of cone outer segments in M-cone photoreceptor cells. Despite the loss of cone outer segments, cone photoreceptor cells remained viable, even up to 6 months of age in hemizygous and homozygous mutant mice. Thus, in contrast to rhodopsin mutants, the M-opsin mutant does not appear to form toxic aggregates that cause cone photoreceptor cell death.