Abstract
Retinitis pigmentosa (RP), a common group of human
retinopathic diseases, is characterized by late-onset night blindness,
loss of peripheral vision, and diminished or absent
electroretinogram (ERG) responses. Mutations in the
photoreceptor-specific gene
RP1
account for 5–10% of
cases of autosomal dominant RP. We generated a mouse model of
the RP1 form of RP by targeted disruption of the mouse ortholog
(
Rp1
) of human
RP1
. In
Rp1
−/−
mice, the number of rod
photoreceptors decreased progressively over a period of 1 year, whereas
that of cone photoreceptors did not change for at least 10 months.
Light and electron microscopic analysis revealed that outer segments of
Rp1
−/−
rods and cones were
morphologically abnormal and became progressively shorter in length.
Before photoreceptor cell death, rhodopsin was mislocalized in inner
segments and cell bodies of
Rp1
−/−
rods.
Rod ERG amplitudes of
Rp1
−/−
mice were
significantly smaller than those of
Rp1
+/+
mice over a period of 12 months, whereas those of
Rp1
+/−
mice were intermediate. The
decreases in cone ERG amplitudes were slower and less severe than those
in rods. These findings demonstrate that Rp1 is required for normal
morphogenesis of photoreceptor outer segments and also may play a role
in rhodopsin transport to the outer segments. The phenotype of
Rp1
mutant mice resembles the human RP1 disease. Thus,
these mice provide a useful model for studies of RP1 function, disease
pathology, and therapeutic interventions.