Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss

Pater, Justin A.; Green, Jane; O’Rielly, Darren D.; Griffin, Anne; Squires, Jessica; Burt, Taylor; Fernández, Sara Pereiro; Fernandez, Bridget A.; Houston, Jim; Zhou, Jiayi; Roslin, Nicole M.; Young, Terry‐Lynn

doi:10.1186/s12881-019-0777-z

Cited by 10 publications

(12 citation statements)

References 30 publications

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“…In a previously published analysis of translational read-through of fibroblasts that were derived from a patient suffering for Niemann-Pick A/B, the SIFT prediction was also in agreement with the biochemical results obtained, whereas the Polyphen-2 gave the opposite results [50]. Although, in silico prediction programs are frequently used, they may be erroneous in determining the specific effect of a likely pathogenic variant, yet [51]. Therefore, they should be interpreted with caution and should not be taken as a definitive approach [50].…”

Section: Discussionsupporting

confidence: 71%

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: Discussionsupporting

confidence: 71%

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

Samanta

Štingl

Kohl

et al. 2019

IJMS

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“…The p.(Cys759Phe) mutation—pathologic variant in the Spanish population—displays consistent genotype-phenotype correlations in for both nonsyndromic RP and USH2A. These patients display different age at diagnosis of RP and of hypoacusis depending on whether they are homozygous for this variant, compound heterozygous for this variant and a missense variant, or compound heterozygous for this variant with an additional truncating variant; legal blindness and hearing loss occurs earlier in heterozygous patients than in homozygous patients (49 vs 62 years for blindness and 53 vs 70 years for hearing loss, respectively) (Pérez-Carro et al 2018). Studies of two newly identified USH2A variants in two Korean families have demonstrated more profound and progressive hearing loss than expected for USH2, requiring cochlear implantation (Lee et al 2019).…”

Section: Usher Syndrome Type IImentioning

confidence: 99%

Review of Genotype-Phenotype Correlations in Usher Syndrome

et al. 2021

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Usher syndrome (USH) encompasses a group of clinically and genetically heterogenous disorders defined by the triad of sensorineural hearing loss (SNHL), vestibular dysfunction, and vision loss. USH is the most common cause of deaf blindness. USH is divided clinically into three subtypes—USH1, USH2, and USH3—based on symptom severity, progression, and age of onset. The underlying genetics of these USH forms are, however, significantly more complex, with over a dozen genes linked to the three primary clinical subtypes and other atypical USH phenotypes. Several of these genes are associated with other deaf-blindness syndromes that share significant clinical overlap with USH, pointing to the limits of a clinically based classification system. The genotype-phenotype relationships among USH forms also may vary significantly based on the location and type of mutation in the gene of interest. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to USH. Currently, the state of knowledge varies widely depending on the gene of interest. Recent studies utilizing next-generation sequencing technology have expanded the list of known pathogenic mutations in USH genes, identified new genes associated with USH-like phenotypes, and proposed algorithms to predict the phenotypic effects of specific categories of allelic variants. Further work is required to validate USH gene causality, and better define USH genotype-phenotype relationships and disease natural histories—particularly for rare mutations—to lay the groundwork for the future of USH treatment.

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“…Thus, USH2A mutations with usher syndrome type IIA and an association of genotype/phenotype have been successfully linked in the patient of the studied family. Pater et al (46) recently reassigned the diagnosis of usher syndrome by identifying novel USH2A splicing variants. To the best of our knowledge, the USH2A variants c.T449G (p.L150*), c.T10695A (p.Y3565*) are novel, thereby extending the spectrum of known mutations associated with this disease.…”

Section: Discussionmentioning

confidence: 99%

Novel compound heterozygous nonsense variants, p.L150* and p.Y3565*, of the USH2A gene in a Chinese pedigree are associated with Usher syndrome type�IIA

Cheng

Zhou

et al. 2020

Mol Med Rep

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usher syndrome refers to a group of genetically and clinically heterogeneous autosomal recessive diseases with retinitis pigmentosa (RP) and hearing deficiencies. The association between usher syndrome-causative genes and resultant Usher syndrome phenotypes in patients are highly variable. In the present study, a chinese family with usher syndrome was recruited, and targeted next-generation sequencing, Sanger sequencing and segregation analysis were performed. The expression profiles and functional effects of the pathogenic variants of USH2A identified were analyzed. Novel nonsense compound heterozygous variants, c.T449G (p.L150*) and c.T10695A (p.Y3565*), were identified in the USH2A gene, which showed co-segregation with the disease phenotype causing usher syndrome type iia in the recruited chinese pedigree. The p.L150* variant was predicted to produce a truncated protein which lacked almost all the functional domains of USH2A, whereas the p.Y3565* variant is located in one of the fibronectin type 3 domains, resulting in the loss of several fibronectin type 3 domains at the C-terminus of USH2A by producing the truncated protein. It was shown that Ush2a mrna expression levels were higher in the retina compared with those in the eye tissues (lens, sclera and cornea), uterus, ovary, breast, testis, spleen, kidney, liver, intestine, brain, skeletal muscle and blood. Additionally, the protein structure was shown to be highly conserved by comparing Homo sapiens USH2A to eight other species. To the best of our knowledge, the present study is the first to identify two novel pathogenic variants, c.T449G (p.L150*) and c.T10695A (p.Y3565*), in the USH2A gene in a patient with usher syndrome type iia, thereby expanding the known spectrums of USH2A causative mutations. The present discovery may assist in understanding the molecular pathogenesis underlying the development of rP and usher syndrome type iia, and in the development of diagnostic, therapeutic and genetic counseling strategies in patients with Usher syndrome type IIA disease.

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Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss

Cited by 10 publications

References 30 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

Review of Genotype-Phenotype Correlations in Usher Syndrome

Novel compound heterozygous nonsense variants, p.L150* and p.Y3565*, of the USH2A gene in a Chinese pedigree are associated with Usher syndrome type�IIA

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