Genetics of Usher Syndrome: New Insights From a Meta-analysis

Jouret, Guillaume; Poirsier, Céline; Spodenkiewicz, Marta; Jaquin, Clémence; Gouy, Evan; Arndt, Carl; Labrousse, M.; Gaillard, Dominique; Doco‐Fenzy, Martine; Lèbre, Anne-Sophie

doi:10.1097/mao.0000000000002054

Cited by 66 publications

(60 citation statements)

References 72 publications

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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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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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“…Perhaps the polygenetic/modifier genes, such as gene PDZD7 or other undetected modifier genes, play a role in the disease phenotypes. Those unknown modifier genes could be pivotal contributors specific to non-syndromic RD, or complete USH II [2]. The other reported mutation, c.5572+1G>A, has been detected in a Scandinavian USH II patient [26].…”

Section: Discussionmentioning

confidence: 94%

“…Most patients have non-syndromic RP, while others suffer from associated syndromes. 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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“…Genetic screening and the accurate diagnosis of Usher syndrome in different populations is necessary (Ben-Rebeh et al, 2016;Sun et al, 2018;Santana et al, 2019). Efficient molecular diagnosis of Usher syndrome in a patient's early childhood is of utmost importance, allowing better genetic counseling and therapeutic management (Ben-Rebeh et al, 2016;Ivanova et al, 2018;Maddalena et al, 2018;Jouret et al, 2019). With accurate gene diagnosis for Usher syndrome, the repair of specific mutations using a CRISPR/Cas9 editing system may be possible.…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the CDH23 Gene Causing Usher Syndrome Type ID in a Chinese Patient

et al. 2020

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Usher syndrome includes a group of genetically and clinically heterogeneous autosomal recessive diseases, such as retinitis pigmentosa (RP) and sensorineural hearing loss. Usher syndrome type I (USHI) is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to RP. The relationships between the Usher syndrome causing genes and the resultant phenotypes of Usher syndrome have not yet been fully elucidated. In the present study, we recruited a Chinese family with Usher syndrome and conducted paneled next-generation sequencing, Sanger sequencing, segregation analysis, and expression profile analysis. The functional effects of the identified cadherin-related 23 (CDH23) pathogenic variants were analyzed. The M101 pedigree consisted of a proband and seven family members, and the proband was a 39-year-old Chinese male who claimed that he first began to experience night blindness 11 years ago. We revealed novel, missense compound heterozygous variants c. 2572G > A (p.V858I) and c. 2891G > A (p.R964Q) in the CDH23 gene, which co-segregated with the disease phenotype causing Usher syndrome type ID (USH1D) in this Chinese pedigree. CDH23 mRNA was highly expressed in the retina, and this protein was highly conserved as revealed by the comparison of Homo sapiens CDH23 with those from nine other species. This is the first study to identify the novel, missense compound heterozygous variants c. 2572G > A (p.V858I) and c.2891G > A (p.R964Q) of CDH23, which might cause USH1D in the studied Chinese family, thereby extending CDH23 mutation spectra. Identifying CDH23 pathogenic variants should help in the detailed phenotypic characterization of USH1D.

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Genetics of Usher Syndrome: New Insights From a Meta-analysis

Cited by 66 publications

References 72 publications

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

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

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the CDH23 Gene Causing Usher Syndrome Type ID in a Chinese Patient

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