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.2008 Aug 1;17(15):2405-15.
doi: 10.1093/hmg/ddn140. Epub 2008 May 7.

Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism

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Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism

Samuel G Jacobson et al. Hum Mol Genet..

Abstract

Usher syndrome (USH) is a genetically heterogeneous group of autosomal recessive deaf-blinding disorders. Pathophysiology leading to the blinding retinal degeneration in USH is uncertain. There is evidence for involvement of the photoreceptor cilium, photoreceptor synapse, the adjacent retinal pigment epithelium (RPE) cells, and the Crumbs protein complex, the latter implying developmental abnormalities in the retina. Testing hypotheses has been difficult in murine USH models because most do not show a retinal degeneration phenotype. We defined the retinal disease expression in vivo in human USH using optical imaging of the retina and visual function. In MYO7A (USH1B), results from young individuals or those at early stages indicated the photoreceptor was the first detectable site of disease. Later stages showed photoreceptor and RPE cell pathology. Mosaic retinas in Myo7a-deficient shaker1 mice supported the notion that the mutant photoreceptor phenotype was cell autonomous and not secondary to mutant RPE. Humans with PCDH15 (USH1F), USH2A or GPR98 (USH2C) had a similar retinal phenotype to MYO7A (USH1B). There was no evidence of photoreceptor synaptic dysfunction and no dysplastic phenotype as in CRB1 (Crumbs homologue1) retinopathy. The results point to the photoreceptor cell as the therapeutic target for USH treatment trials, such as MYO7A somatic gene replacement therapy.

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Figures

Figure 1.
Figure 1.
HumanMYO7A-mutant retinas analyzed for photoreceptor (PR) and retinal pigment epithelium (RPE) disease.En face images of infrared reflectance in a normal (A) and an USH1B subject (B) with superimposed cross-sectional images and insets (upper right) of PR (outer nuclear layer, ONL) topography. Arrow (B, lower right) points to pigment migration in the USH1B image. (C) Vertical cross-sections of a normal subject and twoMYO7A-mutant retinas with advanced disease. Reflectivity profiles (white lines) are overlaid on the section at 4.1 mm in superior retina. Highlighted are ONL (blue) and inner/outer segment (IS/OS) layer (yellow). (D) Reflectivity profiles with signal features representing PR (ONL, blue; IS/OS, yellow) and RPE (sub-RPE backscatter index, gray) are shown. (E) Quantitation of the PR and RPE parameters derived from cross-sections at the superior retinal locus in fiveMYO7A-mutant retinas at advanced stages compared with results from a normal population (N;n = 26; ages 5–68 years). PR abnormalities in theMYO7A data co-localize with abnormal RPE (asterisk; significantly reduced for PR or increased for RPE). Error bars on normal are ±2SD from mean normal parameters. F, fovea; T, temporal; N, nasal; S, superior.
Figure 2.
Figure 2.
MYO7A-mutant retinas at early ages and stages show photoreceptor (PR) before retinal pigment epithelium (RPE) disease expression. (A) Optical scans of the central-superior retina (inset, right) in three young USH1B subjects show preserved PR lamination; longitudinal data in two of the individuals (F1,P2 over 7 years; F2,P1 over 8 years) show diminution of superior extent. For comparison, the scan from F4,P1, a 35-year-old USH1B subject, is shown. (B) Quantitation of the PR and RPE signals from the scans at 4.1 mm in the superior retina in normal subjects (N;n = 26; ages 5–68) compared with theMYO7A-mutant retinas. PR parameters become significantly reduced (asterisk), while the RPE parameter remains within normal limits except in F4,P1 at age 35 years, in which both parameters are abnormal. F, fovea; S, superior.
Figure 3.
Figure 3.
Photoreceptor phenotype in shaker1 mice is associated with lack of photoreceptor (PR) MYO7A, and is not secondary to retinal pigment epithelium (RPE) defect. (A) Light micrograph of a mosaic retina, showing wild-type (WT) (black horizontal bars) and mutant (white horizontal bars) RPE cells, as indicated by the distribution of the melanosomes. Short vertical white bars indicate the apical region, which is devoid of melanosomes in the mutant cells (and contains melanosomes in the WT cells). Scale bar (upper right) = 10 µm. (B) Electron micrograph of the connecting cilium (CC) and basal outer segment (OS) discs of a PR in a mosaic retina. The section was double-labeled with opsin antibodies (identified by goat anti-mouse (GAM) IgG, conjugated to 5 nm gold particles) and MYO7A antibodies (identified by goat anti-rabbit IgG, conjugated to 10 nm gold particles). The presence of MYO7A indicates that this PR cell expressed theMyo7a transgene. The PR was adjacent to a mutant RPE cell (data not shown). The scarcity of opsin label in the CC (only two 5 nm particles are evident, indicated by arrowheads) is consistent with a WT phenotype. (C) Electron micrograph of the CC and basal OS discs of a PR in aMyo7a-null retina. The section was labeled with opsin antibodies (identified by GAM IgG, conjugated to 10 nm gold particles). In the absence of MYO7A, the CC contains significant opsin label, as shown previously (12). Scale bars in B and C = 100 nm. (D) Bar graph showing opsin immunogold particle density measured in the PR connecting cilia of (from left to right): WT retinas; MYO7A-null retinas; three different mosaic retinas, with counts separated for photoreceptors interfacing with normal RPE (WT; shaded bars) and those interfacing with mutant RPE (Mu; filled bars), as determined by the distribution of the melanosomes (13). These data indicate that the genotype of the RPE cell has no significant effect on the quantity of opsin label in the connecting cilia. The last two bars show opsin immunogold particle density according to whether a given CC was also labeled with MYO7A antibodies. The PR cilia that were labeled with MYO7A antibodies (Pr WT) showed opsin labeling that was similar to that in WT retinas (e.g. panel B), whereas the cilia that were not labeled with MYO7A antibodies (Pr Mu) had opsin labeling that was more comparable with that in MYO7A-null retinas. A minimum of 20 PR cells was counted in each retina. Data for the first two and last two bars were obtained from three animals of each genotype. Error bars indicate ±SEM. Studentt-test analysis showed no significant difference between counts for photoreceptors interfacing with normal RPE and those interfacing with mutant RPE in mosaic retinas. There was also no significant difference between photoreceptors in WT retinas and MYO7A-labeled photoreceptors in mosaic retinas; and between photoreceptors in MYO7A-null retinas and photoreceptors that were not labeled with MYO7A antibodies in mosaic retinas.
Figure 4.
Figure 4.
Photoreceptor (PR) structure is lost before retinal pigment epithelium (RPE) disease is structurally apparent in all Usher syndrome (USH) genotypes. (A–C) Optical scans of the central-superior retina in multiple individuals within each genotype (USH2A,GPR98) or longitudinal measurements in the same individual (PCDH15 over a decade). Quantitation of PR and RPE signals shows PR losses without or with RPE abnormalities but no examples of RPE abnormalities preceding PR loss. The spectrum of ages of individuals withUSH2A available for study reveals a proposed disease sequence from normal PR and RPE to abnormalities in only PR to disease in both layers. The family withGPR98-mutant retina also reveals this spectrum of changes. F, fovea; S, superior. (D) ONL (outer nuclear layer) thickness is plotted as a function of sub-RPE backscatter index in the four USH genotypes (key) at the superior retinal locus. Data from longitudinal measurements are connected by dashed lines. Normal variability is described by the ellipse encircling 95% confidence interval of a bivariate Gaussian distribution. Unfilled circles, normal subjects (n = 25; ages 5–58 years).
Figure 5.
Figure 5.
Usher syndrome (USH) genotypes: testing hypotheses about dysfunction at the photoreceptor (PR) synapse and interaction with the Crumbs network. (A) Relationship between PR nuclear layer structure [outer nuclear layer (ONL) thickness] and visual function (dark-adapted sensitivity, 500 nm) at superior (left) and temporal (right) retinal loci (insets at upper right: loci, filled circle; fovea, cross). USH genotypes (filled symbols) are compared with CSNB (congenital stationary night blinding) genotypes (unfilled symbols with ‘plus’), diseases that compromise synaptic transmission from PRs to second-order neurons. Data from 11 individuals with adRP Class Brhodopsin mutations are also shown (gray circles) (18,19). Normal variability is described by ellipses encircling the 95% confidence interval of a bivariate Gaussian distribution. Dashed lines indicate the idealized model of the relationship between structure and function in pure PR degenerations and the region of uncertainty that results by translating the normal variability along the idealized model (20). (B) Cross-sectional OCT (optical coherence tomography) scans along the horizontal meridian (upper) anden face infrared reflectance images (lower) for a normal subject (top left), a subject with aCRB1 mutation (top right), and subjects withMYO7A orUSH2A mutations (bottom row). Highlighted are ONL (blue) and inner/outer segment (IS/OS) layer (yellow). Dashed white lines on scans indicate mean normal thickness (n = 27). The dysplastic and thickenedCRB1-mutant retina is in contrast to the thinned retinas in USH genotypes.
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References

    1. Maerker T., van Wijk E., Overlack N., Kersten F.F., McGee J., Goldmann T., Sehn E., Roepman R., Walsh E.J., Kremer H., et al. A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum. Mol. Genet. 2008;17:71–86. - PubMed
    1. Lefèvre G., Michel V., Weil D., Lepelletier L., Bizard E., Wolfrum U., Hardelin J.P., Petit C. A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth. Development. 2008;135:1427–1437. - PubMed
    1. Williams D.S. Usher syndrome: animal models, retinal function of Usher proteins, and prospects for gene therapy. Vision Res. 2008;48:433–441. - PMC - PubMed
    1. Hasson T., Hintzelman M.B., Santos-Sacchi J., Corey D.P., Mooseker M.S. Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B. Proc. Natl Acad. Sci. USA. 1995;92:9815–9819. - PMC - PubMed
    1. Liu X., Vansant G., Udovichenko I.P., Wolfrum U., Williams D.S. Myosin VIIa, the product of the Usher 1B syndrome gene, is concentrated in the connecting cilia of photoreceptor cells. Cell Motil. Cytoskeleton. 1997;37:240–252. - PubMed

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