Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa

Pierrache, Laurence; Hartel, Bas P.; Wijk, Erwin van; Meester-Smoor, Magda A.; Cremers, Frans P.M.; Baere, Elfride De; Zaeytijd, Julie De; Schooneveld, Mary J. van; Cremers, C.W.R.J.; Dagnelie, Gislin; Hoyng, Carel B.; Bergen, Arthur A. B.; Leroy, Bart P.; Pennings, Ronald J.E.; Born, L. Ingeborgh van den; Klaver, Caroline C.W.

doi:10.1016/j.ophtha.2016.01.021

Cited by 80 publications

(102 citation statements)

References 28 publications

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“…This discrepancy might be explained by different age at RP diagnosis in two subjects. Most patients with USH2A-associated RP showed a relatively preserved visual acuity in their thirties or forties, but a higher cumulative risk of visual impairment in their fifties [36,37]. A recent study suggested that subjects with truncating variants could have earlier onset or rapid deterioration of visual phenotype than those with missense mutations [38]; however, this finding was limited by a comparison of the visual phenotypes between subjects carrying truncating variants and subjects with only missense variants.…”

Section: Discussionmentioning

confidence: 99%

Severe or Profound Sensorineural Hearing Loss Caused by Novel USH2A Variants in Korea: Potential Genotype-Phenotype Correlation

Lee

Joo

et al. 2020

Clin Exp Otorhinolaryngol

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Objectives. We, herein, report two novel USH2A variants from two unrelated Korean families and their clinical phenotypes, with attention to severe or more than severe sensorineural hearing loss (SNHL).Methods. Two postlingually deafened subjects (SB237-461, M/46 and SB354-692, F/34) with more than severe SNHL and also with suspicion of Usher syndrome type II (USH2) were enrolled. A comprehensive audiological and ophthalmological assessments were evaluated. We conducted the whole exome sequencing and subsequent pathogenicity prediction analysis.Results. We identified the following variants of USH2A from the two probands manifesting more than severe SNHL and retinitis pigmentosa (RP): compound heterozygosity for a nonsense (c.8176C>T: p.R2723X) and a missense variant (c.1823G>A: p.C608Y) in SB237, and compound heterozygosity for two frameshift variants (c.14835delT: p.S4945fs & c.13112_13115delAAAT: p.G4371fs) in SB354. Based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, two novel variants, c.1823G>A: p.C608Y and c.14835delT: p.Ser4945fs, can be classified as “uncertain significance” and “pathogenic,” respectively. The audiogram exhibited more than severe SNHL and a down-sloping configuration, necessitating cochlear implantation. The ophthalmic examinations revealed typical features of RP. Interestingly, one proband (SB 354-692) carrying two truncating compound heterozygous variants exhibited more severe hearing loss than the other proband (SB 237-461), carrying one truncation with one missense variant.Conclusion. Our results provide insight on the expansion of audiological spectrum encompassing more than severe SNHL in Korean subjects harboring USH2A variants, suggesting that USH2A should also be included in the candidate gene of cochlear implantation. A specific combination of USH2A variants causing truncating proteins in both alleles could demonstrate more severe audiological phenotype than that of USH2A variants carrying one truncating mutation and one missense mutation, suggesting a possible genotype-phenotype correlation. The understanding of audiological complexity associated with USH2A will be helpful for genetic counseling and treatment starategy.

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Section: Discussionmentioning

confidence: 99%

Severe or Profound Sensorineural Hearing Loss Caused by Novel USH2A Variants in Korea: Potential Genotype-Phenotype Correlation

Lee

Joo

et al. 2020

Clin Exp Otorhinolaryngol

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“…USH2A is commonly mutated among the cohort of non-syndromic RP patients and USH2 patients. As mutations in USH2A account for 12%-25% of non-syndromic RP patients and for 55%-90% of USH2 patients, it is one of the most important genes in these rare diseases [9,[39][40][41]. Moreover, 14%-29% of the disease-causing mutations in USH2A are nonsense mutations [42,43]; thus, targeting those mutations would be beneficial for a large cohort of affected individuals.…”

Section: Discussionmentioning

confidence: 99%

Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations

Samanta

Štingl

Kohl

et al. 2019

IJMS

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The identification of genetic defects that underlie inherited retinal diseases (IRDs) paves the way for the development of therapeutic strategies. Nonsense mutations caused approximately 12% of all IRD cases, resulting in a premature termination codon (PTC). Therefore, an approach that targets nonsense mutations could be a promising pharmacogenetic strategy for the treatment of IRDs. Small molecules (translational read-through inducing drugs; TRIDs) have the potential to mediate the read-through of nonsense mutations by inducing expression of the full-length protein. We provide novel data on the read-through efficacy of Ataluren on a nonsense mutation in the Usher syndrome gene USH2A that causes deaf-blindness in humans. We demonstrate Ataluren´s efficacy in both transiently USH2AG3142*-transfected HEK293T cells and patient-derived fibroblasts by restoring USH2A protein expression. Furthermore, we observed enhanced ciliogenesis in patient-derived fibroblasts after treatment with TRIDs, thereby restoring a phenotype that is similar to that found in healthy donors. In light of recent findings, we validated Ataluren´s efficacy to induce read-through on a nonsense mutation in USH2A-related IRD. In line with published data, our findings support the use of patient-derived fibroblasts as a platform for the validation of preclinical therapies. The excellent biocompatibility combined with sustained read-through efficacy makes Ataluren an ideal TRID for treating nonsense mutations based IRDs.

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“…Few studies have been conducted on the visual prognosis and genotype-phenotype correlations in retinal degeneration arising from USH2A mutations. A Japanese study demonstrated that patients with USH2A-associated USH II showed an earlier decline in visual function and had a higher cumulative risk of visual impairment than those with non-syndromic RP [5]. Complete loss of the USH2A protein function predisposed subjects to USH II, but residual protein function could cause RP without HL.…”

Section: Discussionmentioning

confidence: 99%

“…The most common of these is Usher syndrome (USH) [2], an autosomal recessive disorder that has a prevalence of 3.2-6.2/100000 and is characterized by sensorineural hearing loss (HL), visual impairment due to RP, and variable vestibular dysfunction with heterogeneous clinical and genetic manifestations [3,4]. Mutations in the Usher syndrome 2A (USH2A) gene give rise to two distinct phenotypes, USH type II (USH II) and non-syndromic RP, which account for 55-90% [2] and 12-25% [5] of cases, respectively.…”

Section: Introductionmentioning

confidence: 99%

Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing

Jin

Long

et al. 2020

Bioscience Reports

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Background: The USH2A gene encodes usherin, a basement membrane protein that is involved in the development and homeostasis of the inner ear and retina. Mutations in USH2A are linked to Usher syndrome type II (USH II) and non-syndromic retinitis pigmentosa (RP). Molecular diagnosis can provide insight into the pathogenesis of these diseases, facilitate clinical diagnosis, and identify individuals who can most benefit from gene or cell replacement therapy. Here, we report 21 pathogenic mutations in the USH2A gene identified in 11 Chinese families by using the targeted next-generation sequencing (NGS) technology. Methods: In all, 11 unrelated Chinese families were enrolled, and NGS was performed to identify mutations in the USH2A gene. Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations in these families. Results: We identified 21 pathogenic mutations, of which 13, including 5 associated with non-syndromic RP and 8 with USH II, have not been previously reported. The novel variants segregated with disease phenotype in the affected families and were absent from the control subjects. In general, visual impairment and retinopathy were consistent between the USH II and non-syndromic RP patients with USH2A mutations. Conclusions: These findings provide a basis for investigating genotype–phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.

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Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa

Cited by 80 publications

References 28 publications

Severe or Profound Sensorineural Hearing Loss Caused by Novel <i>USH2A</i> Variants in Korea: Potential Genotype-Phenotype Correlation

Severe or Profound Sensorineural Hearing Loss Caused by Novel <i>USH2A</i> Variants in Korea: Potential Genotype-Phenotype Correlation

Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations

Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing

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