Retinal Degeneration in Usher Syndrome

2007 ◽  
pp. 137-148
Author(s):  
David S. Williams
Keyword(s):  
Retinal Degeneration ◽  
Usher Syndrome

scholarly journals Gene therapy approaches for prevention of retinal degeneration in Usher syndrome

Gene Therapy ◽  
2017 ◽  
Vol 24 (2) ◽  
pp. 68-71 ◽  
Author(s):  
D S Williams ◽  
A Chadha ◽  
R Hazim ◽  
D Gibbs
Keyword(s):  
Gene Therapy ◽  
Retinal Degeneration ◽  
Usher Syndrome

scholarly journals The Time Course of Deafness and Retinal Degeneration in a Kunming Mouse Model for Usher Syndrome

PLoS ONE ◽  
2016 ◽  
Vol 11 (5) ◽  
pp. e0155619 ◽  
Author(s):  
Lu Yao ◽  
Lei Zhang ◽  
Lin-Song Qi ◽  
Wei Liu ◽  
Jing An ◽  
...  
Keyword(s):  
Mouse Model ◽  
Retinal Degeneration ◽  
Time Course ◽  
Usher Syndrome ◽  
Kunming Mouse

scholarly journals A Natural Occurring Mouse Model with Adgrv1 Mutation of Usher Syndrome 2C and Characterization of its Recombinant Inbred Strains

2018 ◽  
Vol 47 (5) ◽  
pp. 1883-1897 ◽  
Author(s):  
Weiming Yan ◽  
Pan Long ◽  
Tao Chen ◽  
Wei Liu ◽  
Lu Yao ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Retinal Degeneration ◽  
Western Blotting ◽  
Hair Cells ◽  
Recombinant Inbred ◽  
Usher Syndrome ◽  
Inbred Strains ◽  
Outer Hair Cells ◽  
Recombinant Inbred Strains

Background/Aims: Our laboratory discovered a Kunming mouse with enormous electroretinogram (ERG) defects. Its auditory brainstem response (ABR) threshold was significantly elevated and closely resembled the features of Usher syndrome (USH). This study sought to cross these USH-like mice (named KMush/ush mice) with CBA/CaJ mice to establish recombinant inbred strains and identify their phenotypes and genotypes. Methods: KMush/ush mice were crossed with CBA/CaJ mice to establish inbred strains by sibling mating. ERG, ABR, ocular fundus morphology, histological examinations of the retina and inner ear, quantitative real-time polymerase chain reaction, western blotting, and exon sequencing were performed to assess the phenotypes and genotypes of the offspring strains. Results: The F1 hybrids from crossing KMush/ush and CBA/CaJ mice had normal ERG and ABR responses. The F2 offspring from intercrossing the F1 mice showed a segregation of the retinitis pigmentosa (RP) and hearing loss phenotypes. The CBA-1ush/ush mice had an RP phenotype that was characterized by a vanished ERG waveform and loss of the outer nuclear layer. Their Pde6b gene had a nonsense mutation that resulted in the failure of protein production in western blotting. However, the ABR threshold of this strain of mice was normal. The CBA-2ush/ush mice had normal retinal function and architecture. Their ABR threshold was increased, with a dramatic degeneration of the stereocilia bundles in the outer hair cells of the inner ear. Whole exome sequencing and exon sequencing revealed a deletion of one base pair in exon 31 of the Adgrv1 gene, which would result in the premature termination of protein encoding. The level of Adgrv1 mRNA was reduced in the CBA-2ush/ush mice. The CBA-3ush/ush mice had phenotypes of RP, elevated ABR threshold, and degeneration of the stereocilia bundles in the outer hair cells. They were closely associated with the nonsense mutations of Pde6b and Adgrv1, respectively. Conclusion: We isolated a mouse strain with hearing loss from inbred mice with retinal degeneration and established it as a recombinant inbred strain with a spontaneous mutation in Adgrv1, the human Usher syndrome 2C gene. The retinal degeneration was cause by a mutation in Pde6b, while the hearing loss was caused by a mutation in Adgrv1.

scholarly journals Potential therapy for progressive vision loss due to PCDH15-associated Usher syndrome developed in an orthologous Usher mouse

2021 ◽  
Author(s):  
Saumil Sethna ◽  
Wadih M Zein ◽  
Sehar Riaz ◽  
Arnaud P.J. Giese ◽  
Julie M Schultz ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Usher Syndrome ◽  
Visual Field Loss ◽  
Type I ◽  
Ashkenazi Jews ◽  
Visual Deficits ◽  
Protocadherin 15

Usher syndrome type I (USH1) is characterized by congenital deafness, vestibular areflexia, and progressive retinal degeneration with age. The protein-truncating p.Arg245* founder variant of PCDH15 has an ~2% carrier frequency among Ashkenazi Jews, accounting for nearly 60% of their USH1 cases. Here, longitudinal ocular phenotyping in thirteen USH1F individuals harboring the p.Arg245* variant revealed progressive retinal degeneration, leading to severe loss of vision with macular atrophy by the sixth decade. Half of the affected individuals met either the visual acuity or visual field loss definition for legal blindness by the middle of their fifth decade of life. Mice homozygous for p.Arg250* (Pcdh15R250X; equivalent to human p.Arg245*) also have early visual deficits evaluated using electroretinography. Light-dependent translocation of phototransduction cascade proteins, arrestin and transducin, was found to be impaired in Pcdh15R250X mice. Retinal pigment epithelium- (RPE) specific visual retinoid cycle proteins, RPE65 which converts all-trans retinoids to 11-cis retinoids and CRALBP that transports retinoids, and key retinoid levels were also reduced in Pcdh15R250X mice, suggesting a dual role for protocadherin-15 in photoreceptors and RPE. Administration of exogenous 9-cis retinal, an analog of the naturally occurring 11-cis retinal, improved ERG amplitudes in these mutant mice, suggesting a basis for a clinical trial of exogenous FDA approved retinoids to preserve vision in USH1F patients.

scholarly journals Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher Syndrome

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Saumil Sethna ◽  
Wadih M Zein ◽  
Sehar Riaz ◽  
Arnaud PJ Giese ◽  
Julie M Schultz ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Usher Syndrome ◽  
Type I ◽  
Ashkenazi Jews ◽  
Visual Deficits ◽  
Severe Vision Loss ◽  
Protocadherin 15

Usher syndrome type I (USH1) is characterized by deafness, vestibular areflexia and progressive retinal degeneration. The protein-truncating p.Arg245* founder variant of PCDH15 (USH1F) has an ~2% carrier frequency amongst Ashkenazi Jews accountings for ~60% of their USH1 cases. Here, longitudinal phenotyping in thirteen USH1F individuals revealed progressive retinal degeneration, leading to severe vision loss with macular atrophy by the sixth decade. Half of the affected individuals were legally blind by their mid-fifties. The mouse Pcdh15R250X variant is equivalent to human p.Arg245*. Homozygous Pcdh15R250X mice also have visual deficits and aberrant light-dependent translocation of the phototransduction cascade proteins, arrestin and transducin. Retinal pigment epithelium- (RPE) specific retinoid cycle proteins, RPE65 and CRALBP, were also reduced in Pcdh15R250X mice, indicating a dual role for protocadherin-15 in photoreceptors and RPE. Exogenous 9-cis retinal improved ERG amplitudes in Pcdh15R250X mice, suggesting a basis for a clinical trial of FDA approved retinoids to preserve vision in USH1F patients.

scholarly journals Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice

2012 ◽  
Vol 199 (2) ◽  
pp. 381-399 ◽  
Author(s):  
Iman Sahly ◽  
Eric Dufour ◽  
Cataldo Schietroma ◽  
Vincent Michel ◽  
Amel Bahloul ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Outer Segment ◽  
Usher Syndrome ◽  
Retinal Dystrophy ◽  
Photoreceptor Cells ◽  
Type I ◽  
Photoreceptor Outer Segment ◽  
Membrane Interfaces ◽  
Protocadherin 15 ◽  
Cadherin 23

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.

scholarly journals Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment

2021 ◽  
Author(s):  
Paulina Bahena ◽  
Narsis Daftarian ◽  
Reza Maroofian ◽  
Paola Linares ◽  
Daniel Villalobos ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Retinal Degeneration ◽  
Hearing Impairment ◽  
Molecular Diagnosis ◽  
Usher Syndrome ◽  
Retinal Dystrophy ◽  
Treatment Modalities ◽  
Ophthalmological Examination ◽  
Sensory Impairment ◽  
Dual Sensory Impairment

AbstractUsher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf–blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15%) probands displayed other genetic entities with dual sensory impairment, including Alström syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf–blind cohort was 92%. Two (3%) probands were partially solved and only 3 (5%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities.

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