Deafness and retinal degeneration in a novel USH1C knock‐in mouse model

Lentz, Jennifer J; Gordon, William C.; Farris, Hamilton E.; MacDonald, Glen; Cunningham, Dale E.; Robbins, Carol A.; Tempel, Bruce L.; Bazán, Nicolás G.; Rubel, Edwin W.; Oesterle, Elizabeth C.; Keats, Bronya J.B.

doi:10.1002/dneu.20771

Cited by 52 publications

(62 citation statements)

References 53 publications

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“…Among all reported USH1 and USH3 mouse models, the Ush1c knock-in mouse is the only one to have a spontaneous retinal degeneration phenotype [161], mimicking the RP symptoms of USH1 patients. In this knock-in mouse, a c.216G>A cryptic splice site mutation in USH1C , cloned from Acadian USH1 patients in Louisiana, was inserted into the mouse genome to replace the normal mouse Ush1c sequence [162].…”

Section: Functional Studies Of Ush Gene Productsmentioning

confidence: 99%

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

Mathur

Yang

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

278

301

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Usher syndrome (USH), clinically and genetically heterogeneous, is the leading genetic cause of combined hearing and vision loss. USH is classified into three types, based on the hearing and vestibular symptoms observed in patients. Sixteen loci have been reported to be involved in the occurrence of USH and atypical USH. Among them, twelve have been identified as causative genes and one as a modifier gene. Studies on the proteins encoded by these USH genes suggest that USH proteins interact among one another and function in multiprotein complexes in vivo. Although their exact functions remain enigmatic in the retina, USH proteins are required for the development, maintenance and function of hair bundles, which are the primary mechanosensitive structure of inner ear hair cells. Despite the unavailability of a cure, progress has been made to develop effective treatments for this disease. In this review, we focus on the most recent discoveries in the field with an emphasis on USH genes, protein complexes and functions in various tissues as well as progress toward therapeutic development for USH.

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Section: Functional Studies Of Ush Gene Productsmentioning

confidence: 99%

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

Mathur

Yang

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

278

301

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“…The authors used a mouse model of human Usher Syndrome 1C which affects harmonin (68, 69), a component of the hair cell transduction complex (70). The mouse model was generated to mimic a recessive mutation in French-Acadian USH1C patients that introduces a cryptic splice site and results in a severely truncated protein (67, 71). Lentz et al (67) screened 47 different ASO sequences for those that could block cryptic splicing and promote correct splicing of the harmonin mRNA transcript.…”

Section: Molecular Therapies For Genetic Hearing Lossmentioning

confidence: 99%

Sound Strategies for Hearing Restoration

Géléoc

Holt

2014

Science

194

122

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Hearing loss is the most common sensory deficit in humans with some estimates suggesting up to 300 million affected individuals worldwide. Both environmental and genetic factors contribute to hearing loss and can cause death of sensory cells and neurons. Since these cells do not regenerate, the damage tends to accumulate leading to profound deafness. Several biological strategies to restore auditory function are currently under investigation. Due to the success of cochlear implants, which offer partial recovery of auditory function for some profoundly deaf patients, potential biological therapies must extend hearing restoration to include greater auditory acuity and larger patient populations. Here we review the latest gene, stem-cell, and molecular strategies for restoring auditory function in animal models and the prospects for translating these approaches into viable clinical therapies.

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“…Among the Usher mouse models that do show a retinal degeneration phenotype, the knock-in mutation for the c.216G > A cryptic splice site mutation in exon 3 of the USH1C gene is an exception. This mouse shows abnormal electroretinograms by 1 month of age, and significant loss of photoreceptors between 6 and 12 months of age (Lentz et al, 2010). The dfcr and ush1c −/− mice, also harboring mutations in the USH1C gene do not have a strong retinal phenotype (Williams, 2008; Williams et al, 2009; Tian et al, 2010), but are deaf.…”

Section: Usher Protein Function In Photoreceptorsmentioning

confidence: 99%

Usher protein functions in hair cells and photoreceptors

Cosgrove¹,

Zallocchi²

2014

The International Journal of Biochemistry & Cell Biology

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The 10 different genes associated with the deaf/blind disorder, Usher syndrome, encode a number of structurally and functionally distinct proteins, most expressed as multiple isoforms/protein variants. Functional characterization of these proteins suggests a role in stereocilia development in cochlear hair cells, likely owing to adhesive interactions in hair bundles. In mature hair cells, homodimers of the Usher cadherins, cadherin 23 and protocadherin 15, interact to form a structural fiber, the tip link, and the linkages that anchor the taller stereocilia's actin cytoskeleton core to the shorter adjacent stereocilia and the elusive mechanotransduction channels, explaining the deafness phenotype when these molecular interactions are perturbed. The conundrum is that photoreceptors lack a synonymous mechanotransduction apparatus, and so a common theory for Usher protein function in the two neurosensory cell types affected in Usher syndrome is lacking. Recent evidence linking photoreceptor cell dysfunction in the shaker 1 mouse model for Usher syndrome to light-induced protein translocation defects, combined with localization of an Usher protein interactome at the periciliary region of the photoreceptors suggests Usher proteins might regulate protein trafficking between the inner and outer segments of photoreceptors. A distinct Usher protein complex is trafficked to the ribbon synapses of hair cells, and synaptic defects have been reported in Usher mutants in both hair cells and photoreceptors. This review aims to clarify what is known about Usher protein function at the synaptic and apical poles of hair cells and photoreceptors and the prospects for identifying a unifying pathobiological mechanism to explain deaf/blindness in Usher syndrome.

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Deafness and retinal degeneration in a novel USH1C knock‐in mouse model

Cited by 52 publications

References 53 publications

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

Sound Strategies for Hearing Restoration

Usher protein functions in hair cells and photoreceptors

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