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: 3.43). 08/2011; 52(11):7924-36. DOI: 10.1167/iovs.11-8313
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Usher syndrome (USH) is the most prevalent cause of inherited deaf-blindness. Three clinical subtypes, USH1-3, have been defined, and ten USH genes identified. The hearing impairment due to USH gene defects has been shown to result from improper organisation of the hair bundle, the sound receptive structure of sensory hair cells. In contrast, the cellular basis of the visual defect is less well understood as this phenotype is absent in almost all the USH mouse models that faithfully mimic the human hearing impairment. Structural and molecular interspecies discrepancies regarding photoreceptor calyceal processes and the association with the distribution of USH1 proteins have recently been unravelled, and have led to the conclusion that a defect in the USH1 protein complex-mediated connection between the photoreceptor outer segment and the surrounding calyceal processes (in both rods and cones), and the inner segment (in rods only), probably causes the USH1 retinal dystrophy in humans.
    Comptes rendus biologies 03/2014; 337(3):167-77. DOI:10.1016/j.crvi.2013.12.004 · 1.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Purpose/Aim: To investigate the relationship of drusen and photoreceptor abnormalities in African-American (AA) patients with intermediate non-neovascular age-related macular degeneration (AMD). Materials and methods: AA patients with intermediate AMD (n = 11; age 52-77 years) were studied with spectral-domain optical coherence tomography. Macular location and characteristics of large drusen (≥125 µm) were determined. Thickness of photoreceptor laminae was quantified overlying drusen and in other macular regions. A patient with advanced AMD (age 87) was included to illustrate the disease spectrum. Results: In this AA patient cohort, the spectrum of changes known to occur in AMD, including large drusen, sub-retinal drusenoid deposits and geographic atrophy, were identified. In intermediate AMD eyes (n = 17), there were 183 large drusen, the majority of which were pericentral in location. Overlying the drusen there was significant thinning of the photoreceptor outer nuclear layer (termed ONL(+)) as well as the inner and outer segments (IS + OS). The reductions in IS + OS thickness were directly related to ONL(+) thickness. In a fraction (∼8%) of paradrusen locations with normal lamination sampled within ∼280 µm of peak drusen height, ONL(+) was significantly thickened compared to age and retinal-location-matched normal values. Topographical maps of the macula confirmed ONL thickening in regions neighboring and distant to large drusen. Conclusions: We confirm there is a pericentral distribution of drusen across AA-AMD maculae rather than the central localization in Caucasian AMD. Reductions in the photoreceptor laminae overlying drusen are evident. ONL(+) thickening in some macular areas of AA-AMD eyes may be an early phenotypic marker for photoreceptor stress.
    Current Eye Research 06/2014; DOI:10.3109/02713683.2014.925934 · 1.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: MYO1A is considered the gene underlying autosomal dominant non-syndromic hearing loss DFNA48, based on six missense variants, one small in-frame insertion and one nonsense mutation. Results from NGS targeting 66 deafness genes in 109 patients identified three families challenging this assumption: Two novel nonsense (p.Tyr740* and p.Arg262*) and a known missense variant were identified heterozygously not only in index patients, but also in unaffected relatives. Deafness in these families clearly resulted from mutations in other genes (MYO7A, EYA1, CIB2). Most of the altogether ten MYO1A mutations are annotated in dbSNP, and population frequencies (dbSNP, 1000 Genomes, Exome Sequencing Project) above 0,1% contradict pathogenicity under a dominant model. One healthy individual was even homozygous for p.Arg262*, compatible with homozygous Myo1a knockout mice lacking any overt pathology. MYO1A seems dispensable for hearing and overall non-essential. MYO1A adds to the list of "erroneous disease genes" which will expand with increasing availability of large-scale sequencing data. This article is protected by copyright. All rights reserved.
    Human Mutation 02/2014; DOI:10.1002/humu.22532 · 5.05 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014