Retinal Disease Course in Usher Syndrome 1B Due to MYO7A Mutations

Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, USA.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 08/2011; 52(11):7924-36. DOI: 10.1167/iovs.11-8313
Source: PubMed


PURPOSE. To determine the disease course in Usher syndrome type IB (USH1B) caused by myosin 7A (MYO7A) gene mutations. METHODS. USH1B patients (n = 33, ages 2-61) representing 25 different families were studied by ocular examination, kinetic and chromatic static perimetry, dark adaptometry, and optical coherence tomography (OCT). Consequences of the mutant alleles were predicted. RESULTS. All MYO7A patients had severely abnormal ERGs, but kinetic fields revealed regional patterns of visual loss that suggested a disease sequence. Rod-mediated vision could be lost to different degrees in the first decades of life. Cone vision followed a more predictable and slower decline. Central vision ranged from normal to reduced in the first four decades of life and thereafter was severely abnormal. Dark adaptation kinetics was normal. Photoreceptor layer thickness in a wide region of central retina could differ dramatically between patients of comparable ages; and there were examples of severe losses in childhood as well as relative preservation in patients in the third decade of life. Comparisons were made between the mutant alleles in mild versus more severe phenotypes. CONCLUSIONS. A disease sequence in USH1B leads from generally full but impaired visual fields to residual small central islands. At most disease stages, there was preserved temporal peripheral field, a potential target for early phase clinical trials of gene therapy. From data comparing patients' rod disease in this cohort, the authors speculate that null MYO7A alleles could be associated with milder dysfunction and fewer photoreceptor structural losses at ages when other genotypes show more severe phenotypes.

Download full-text


Available from: Artur Cideciyan, Oct 03, 2015
35 Reads
  • Source
    • "However, like other retinal degenerations , disease severity varies between patients depending on the MYO7A mutation(s) they carry ( Jacobson et al., 2011). Many USH1B patients retain central retinal structure and function as well as islands of peripheral/temporal field until late stages of the disease ( Jacobson et al., 2011). Detailed analyses of patient genotype and phenotype will therefore be required to understand the safest/most effective temporal and spatial parameters for clinical application of this technology. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Usher syndrome 1B (USH1B) is a severe, autosomal recessive, deaf-blind disorder caused by mutations in MYO7A (myosin 7A). Patients are born profoundly deaf and exhibit progressive loss of vision starting in their first decade. MYO7A is expressed in human photoreceptors and RPE, but disease pathology begins in photoreceptors, highlighting the need to develop a gene replacement strategy that effectively targets this cell type. For its safety and efficacy in clinical trials and ability to transduce postmitotic photoreceptors, we have focused on developing a clinically applicable AAV platform for delivering full-length MYO7A cDNA (~6.7kb). Packaging of full-length MYO7A cDNA in AAV produces vectors with heterogeneous, 'fragmented' genomes ("fAAV") capable of reconstituting full-length cDNA post-infection. We previously showed that fAAV vectors effectively delivered full-length MYO7A in vitro and in vivo. However, fAAV vectors are relatively inefficient and their heterogeneous genomes preclude definitive characterization, a drawback for clinical translatability. The purpose of this study was to overcome these limitations by creating dual AAV vector platforms for USH1B with defined genomes. Human MYO7A was cloned in AAV vector pairs, each containing genomes <5kb and intact inverted terminal repeats (ITRs). One vector contained promoter and 5' portion of the cDNA and the partner vector contained a 3' portion and polyadenylation signal. "Simple overlap" vectors share a central part of the MYO7A cDNA sequence. "Trans-splicing" and "hybrid" vectors utilize splice donor and acceptor sites with and without an additional central recombinogenic sequence, respectively. Vector pairs expressed full-length MYO7A in vitro and in vivo with equal or higher efficiency than fAAV, with a hybrid platform being most efficient. Importantly, analysis of MYO7A mRNA derived from each dual vector platform -revealed 100% fidelity to the predicted sequence. Our results suggest that dual AAV vectors with defined genetic payloads are a potential treatment option for USH1B.
    Human Gene Therapy Methods 02/2014; 25(2). DOI:10.1089/hgtb.2013.212 · 2.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins-myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans-do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner-outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients.
    The Journal of Cell Biology 10/2012; 199(2):381-99. DOI:10.1083/jcb.201202012 · 9.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: To determine the intervisit variability of kinetic visual fields and visual acuity in patients with Leber congenital amaurosis (LCA) caused by mutations in the RPE65 (Retinal Pigment Epithelium-specific protein 65kDa) gene. Methods: RPE65-LCA patients (n = 20; ages 11-40 years) were studied on at least two visits separated by fewer than 120 days using Goldmann visual field (GVF) and ETDRS visual acuity (VA) in a retrospective review. GVFs were quantified by computing the spherical coordinates of their vertices and calculating the solid angle subtended, and reported in normalized solid-angle units (nsu) as a percentage of average normal field extent. Repeatability coefficients were calculated using 95% confidence intervals on log(10)-converted variables. Results: Visual field extents in RPE65-LCA spanned a wide range from 4 to 95 nsu. The repeatability coefficient was 0.248 (log(10)nsu), suggesting cutoffs for significant change (in nsu) of +77% for improvement and -44% for worsening. VA in RPE65-LCA ranged from logMAR = 0.14 to 1.96 (20/40 to 20/1250). The repeatability coefficient was 0.170 (logMAR) (±8.5 ETDRS letters). Comparisons with published studies of ungenotyped retinitis pigmentosa showed that the RPE65-LCA patients had higher variability in kinetic field extent. VA variability in RPE65-LCA fell within reported results for retinitis pigmentosa. Conclusions: Variability data for GVF and VA are provided to permit interpretation of the significance of increases and decreases of these functional outcomes in ongoing and planned clinical trials of therapy for LCA caused by RPE65 mutations.
    Investigative ophthalmology & visual science 01/2013; 54(2). DOI:10.1167/iovs.12-11341 · 3.40 Impact Factor
Show more