To determine the role of SPACR in the pathological mechanisms leading to RP and VMD, we generated a knockout mouse model lacking Impg1, the mouse ortholog. Impg1-deficient mice show abnormal accumulation of autofluorescent deposits visible by fundus imaging and spectral-domain optical coherence tomography (SD-OCT) and attenuated electroretinogram responses from 9 months of age. Furthermore, SD-OCT of Impg1-/- mice shows a degeneration of the photoreceptor layer, and transmission electron microscopy shows a disruption of the IPM and the retinal pigment epithelial cells. The decrease in the concentration of the chromophore 11-cis-retinal supports this loss of photoreceptors. In conclusion, our results demonstrate the essential role of SPACR in maintaining photoreceptors.
ExperimentName: Knockout mouse model of Impg1
NonHumanModel: Mus musculus
GeneAlteration: The mouse model harbors a deletion of exon 6, resulting in disruption of reading frame and loss of Impg1 protein either in the heterozygous or homozygous state.
ModelPhenotype: HP:0025158 (Hyperautofluorescent retinal lesion), HP:0000512 (Abnormal electroretinogram, specifically attenuated responses), HP:0030609 (Photoreceptor layer loss on macular OCT, described as degeneration with loss of 11-cis-retinal signal), HP:0007703 (Abnormality of retinal pigmentation, specifically disruption of RPE cells and the IPM)
HumanPhenotype: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0030505 (Nummular pigmentation of the fundus)
ModelEvidence: The model exhibits phenotypes consistent with a critical role of Impg1 in photoreceptor maintenance. Phenotypes included hyperpigmented and sometimes autofluorescent subretinal deposits that were present at 9 months of age (Figure 2B) and increased by 14 months of age (Figure 2C) that were localized between the photoreceptor outer segment and the RPE (Figure 2D). Some images showed nummular pigmentation of the fundus (Figure 2E). Interestingly, attenuation of ERG response was first noted at 9 months and pronounced at 14 months (Figure 3A), which is consistent with the findings from an independent mouse model that showed less dramatic findings at earlier 5 month and 8 month time points (PMID: 32265257). Scotopic ERG was more affected than photopic ERG (Figure 3B). Retinal thickness was also reduced in the outer layer relative to the inner layer (Figure 3C). Retinoid generation was also progressively abnormal (Figure 4), indicating that photoreceptors might be lost. The IPM was also disorganized at 14 months (Figure 5), with cellular material accumulating in the IPM consistent with cell death (Figure 6).
ModelVariant: The model harbors a knockout allele disrupting Impg1, rather than a specific variant from a human patient.