Knockout of ush2a gene in zebrafish causes hearing impairment and late onset rod-cone dystrophy

Han, Shanshan; Liu, Xiliang; Xie, Shanglun; Gao, Meng; Liu, Fei; Yu, Shanshan; Sun, Peng; Wang, Changquan; Archacki, Stephen; Lu, Zhaojing; Hu, Xuebin; Qin, Yayun; Qu, Zhen; Huang, Yu-Wen; Lv, Yuexia; Tu, Jiayi; Li, Jingzhen; Yimer, Tinsae Assefa; Jiang, Tao; Tang, Zhaohui; Luo, Daji; Chen, Fangyi; Liu, Mugen

doi:10.1007/s00439-018-1936-6

Cited by 42 publications

(42 citation statements)

References 61 publications

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“…It is not fully understood why USH2A variants lead to a wide range of phenotypes and severity of the diseases. Ush2a -knockout in mice and in zebrafish recapitulated a phenotype of human Usher syndrome with retinal degeneration and hearing problems [ 16 , 34 ]. These models could support our observation that all USH2A -RP patients with two truncating variants (n = 6) developed RP and early-onset hearing loss.…”

Section: Discussionmentioning

confidence: 99%

Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients

Inaba

Maeda

Yoshida

et al. 2020

IJMS

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USH2A is a common causal gene of retinitis pigmentosa (RP), a progressive blinding disease due to retinal degeneration. Genetic alterations in USH2A can lead to two types of RP, non-syndromic and syndromic RP, which is called Usher syndrome, with impairments of vision and hearing. The complexity of the genotype–phenotype correlation in USH2A-associated RP (USH2A-RP) has been reported. Genetic and clinical characterization of USH2A-RP has not been performed in Japanese patients. In this study, genetic analyses were performed using targeted panel sequencing in 525 Japanese RP patients. Pathogenic variants of USH2A were identified in 36 of 525 (6.9%) patients and genetic features of USH2A-RP were characterized. Among 36 patients with USH2A-RP, 11 patients had syndromic RP with congenital hearing problems. Amino acid changes due to USH2A alterations were similarly located throughout entire regions of the USH2A protein structure in non-syndromic and syndromic RP cases. Notably, truncating variants were detected in all syndromic patients with a more severe retinal phenotype as compared to non-syndromic RP cases. Taken together, truncating variants could contribute to more serious functional and tissue damages in Japanese patients, suggesting important roles for truncating mutations in the pathogenesis of syndromic USH2A-RP.

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Section: Discussionmentioning

confidence: 99%

Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients

Inaba

Maeda

Yoshida

et al. 2020

IJMS

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“…Usher syndrome-associated visual impairment is the result of RP and presents with night blindness (nyctalopia) and loss of peripheral visual field caused by rod photoreceptor degeneration, progressing to involve cones leading to central vision loss, often resulting in legal blindness ( 16 ). There is significant intra- and inter-familial phenotypic variability, which has recently also been reflected in ush2a zebrafish disease models ( 10 , 17 ). The full-length zebrafish ush2a gene (transcript ID.…”

Section: Introductionmentioning

confidence: 95%

“…However, examination at adult ages was limited and did not reveal clear progressive abnormalities. In contrast, a TALENs-generated ush2a hzu6 zebrafish [c.136_152delGCCCCTCAGGGCAACTT; p.(Ala46Profs * 10), exon 1] was described as showing early defects in ERG and acoustic startle responses with a progressive rod-cone degeneration in the adult fish, apparent from 12 months due to shortening of the photoreceptor outer segments ( 17 ). Levels of rod-specific proteins rhodopsin, GNAT1 and GNB1 were reduced from 7 months.…”

Section: Introductionmentioning

confidence: 99%

Clinical and preclinical therapeutic outcome metrics for USH2A-related disease

Toms

Dubis

Vrieze

et al. 2020

Human Molecular Genetics

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USH2A variants are the most common cause of Usher syndrome type 2, characterized by congenital sensorineural hearing loss and retinitis pigmentosa (RP), and also contribute to autosomal recessive non-syndromic RP. Several treatment strategies are under development; however, sensitive clinical trial endpoint metrics to determine therapeutic efficacy have not been identified. In the present study, we have performed longitudinal retrospective examination of the retinal and auditory symptoms in (i) 56 biallelic molecularly confirmed USH2A patients and (ii) ush2a mutant zebrafish to identify metrics for the evaluation of future clinical trials and rapid preclinical screening studies. The patient cohort showed a statistically significant correlation between age and both rate of constriction for the ellipsoid zone length and hyperautofluorescent outer retinal ring area. Visual acuity and pure tone audiograms are not suitable outcome measures. Retinal examination of the novel ush2au507 zebrafish mutant revealed a slowly progressive degeneration of predominantly rods, accompanied by rhodopsin and blue cone opsin mislocalization from 6 to 12 months of age with lysosome-like structures observed in the photoreceptors. This was further evaluated in the ush2armc zebrafish model, which revealed similar changes in photopigment mislocalization with elevated autophagy levels at 6 days post fertilization, indicating a more severe genotype-phenotype correlation and providing evidence of new insights into the pathophysiology underlying USH2A-retinal disease.

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“…Usherin protein appears to be functional in zebrafish despite them lacking a full-length protein (Dona et al, 2018). In addition, ush2a knockout zebrafish have been generated successfully and these exhibit auditory abnormalities and retinal degeneration, replicating the disease phenotypes of human USH2A patients (Han et al, 2018).…”

Section: Animal Modelsmentioning

confidence: 94%

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

Whatley

Francis

et al. 2020

Front. Genet.

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Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance. Three clinically distinct types of USH have been identified, decreasing in severity from Type 1 to 3, with symptoms of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP), and vestibular dysfunction. There are currently nine confirmed and two suspected USH-causative genes, and a further three candidate loci have been mapped. The proteins encoded by these genes form complexes that play critical roles in the development and maintenance of cellular structures within the inner ear and retina, which have minimal capacity for repair or regeneration. In the cochlea, stereocilia are located on the apical surface of inner ear hair cells (HC) and are responsible for transducing mechanical stimuli from sound pressure waves into chemical signals. These signals are then detected by the auditory nerve fibers, transmitted to the brain and interpreted as sound. Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction. This review summarizes the current knowledge on Usher syndrome with a particular emphasis on mutations in USH genes, USH protein structures, and functional analyses in animal models. Currently, there is no cure for USH. However, the genetic therapies that are rapidly developing will benefit from this compilation of detailed genetic information to identify the most effective strategies for restoring functional USH proteins.

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Knockout of ush2a gene in zebrafish causes hearing impairment and late onset rod-cone dystrophy

Cited by 42 publications

References 61 publications

Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients

Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients

Clinical and preclinical therapeutic outcome metrics for USH2A-related disease

Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy

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