Usher’s Syndrome Type II: A Comparative Study of Genetic Mutations and Vestibular System Evaluation

Magliulo, Giuseppe; Iannella, Giannicola; Gagliardi, Silvia; Iozzo, Nicola; Plateroti, Rocco; Mariottini, Alessandro; Torricelli, Francesca

doi:10.1177/0194599817715235

Cited by 19 publications

(13 citation statements)

References 41 publications

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“…Specifically, HGMDpro (https://portal.biobase-international.com/hgmd/pro/gene.php?gene=ush2a) lists 199 nonsense mutations, which account for 16% of all USH2A mutations. Among them, the p.G3142* mutation was reported recurrently [27,30,31]. The p.G3142* mutation alters the triplet coding for a glycine (GGA) at codon 3142 into a PTC (TGA).…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…In family RP-0605, re-analysis with NGS uncovered the presence of two coexisting retinal diseases (RP and cone affectation), since biallelic pathogenic variants in two different RD-related genes ( USH2A and CNGB3 ) have been identified. These facts bring into consideration the importance of, once the genotype is known, to go back to the phenotype, or curating the phenotype when performing, analysing and reporting molecular studies, and when considering the enrolment of patients into clinical trials [ 56 , 57 ]; moreover, when genetic diseases co-existence has been reported to be present up to 4.9% of cases with informative whole-exome sequencing [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families

et al. 2018

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IntroductionMutations in USH2A cause both isolated Retinitis Pigmentosa (RP) and Usher syndrome (that implies RP and hearing impairment). One of the most frequent variants identified in this gene and among these patients is the p.(Cys759Phe) change. However, the pathogenic role of this allele has been questioned since it was found in homozygosity in two healthy siblings of a Spanish family. To assess the causative role of USH2A p.(Cys759Phe) in autosomal recessive RP (ARRP) and Usher syndrome type II (USH2) and to establish possible genotype-phenotype correlations associated with p.(Cys759Phe), we performed a comprehensive genetic and clinical study in patients suffering from any of the two above-mentioned diseases and carrying at least one p.(Cys759Phe) allele.Materials and methodsDiagnosis was set according to previously reported protocols. Genetic analyses were performed by using classical molecular and Next-Generation Sequencing approaches. Probands of 57 unrelated families were molecularly studied and 63 patients belonging to these families were phenotypically evaluated.ResultsMolecular analysis characterized 100% of the cases, identifying: 11 homozygous patients for USH2A p.(Cys759Phe), 42 compound heterozygous patients (12 of them with another missense USH2A pathogenic variant and 30 with a truncating USH2A variant), and 4 patients carrying the p.(Cys759Phe) allele and a pathogenic variant in another RP gene (PROM1, CNGB1 or RP1). No additional causative variants were identified in symptomatic homozygous patients. Statistical analysis of clinical differences between zygosity states yielded differences (p≤0.05) in age at diagnosis of RP and hypoacusis, and progression of visual field loss. Homozygosity of p.(Cys759Phe) and compound heterozygosity with another USH2A missense variant is associated with ARRP or ARRP plus late onset hypoacusis (OR = 20.62, CI = 95%, p = 0.041).ConclusionsThe present study supports the role of USH2A p.(Cys759Phe) in ARRP and USH2 pathogenesis, and demonstrates the clinical differences between different zygosity states. Phenotype-genotype correlations may guide the genetic characterization based upon specific clinical signs and may advise on the clinical management and prognosis based upon a specific genotype.

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“…While there are known age‐related changes in the cVEMP including absence of the P1‐N1 response that increases from 7% in the fifth decade to 32% in the eighth decade, 35 age did not explain absence of a cVEMP in our USH2A group. Magliulo et al 24 reported bilateral saccular dysfunction in two of five patients with genetically confirmed USH2 (one with mutations in USH2A , one with mutations in ADGRV1) and histories of sporadic vertigo. Here, we extend the observation of saccular dysfunction in USH2A to those with no current or past history of vertigo.…”

Section: Discussionmentioning

confidence: 99%

“…Each Usher syndrome gene is associated with one of the three clinical types. However, there are some reported examples of atypical RP, 10 auditory or vestibular manifestations in patients with variants in genes associated with Usher type I 11‐17 and type II 18‐24 . Some disparity exists because of previous technological limitations in clinical assessment.…”

Section: Introductionmentioning

confidence: 99%

Vestibular phenotype‐genotype correlation in a cohort of 90 patients with Usher syndrome

et al. 2020

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Usher syndrome has been historically categorized into one of three classical types based on the patient phenotype. However, the vestibular phenotype does not infallibly predict which Usher genes are mutated. Conversely, the Usher syndrome genotype is not sufficient to reliably predict vestibular function. Here we present a characterization of the vestibular phenotype of 90 patients with clinical presentation of Usher syndrome (59 females), aged 10.9 to 75.5 years, with genetic variants in eight Usher syndromic genes and expand the description of atypical Usher syndrome. We identified unexpected horizontal semicircular canal reactivity in response to caloric and rotational stimuli in 12.5% (3 of 24) and 41.7% (10 of 24), respectively, of our USH1 cohort. These findings are not consistent with the classical phenotypic definition of vestibular areflexia in USH1. Similarly, 17% (6 of 35) of our cohort with USH2A mutations had saccular dysfunction as evidenced by absent cervical vestibular evoked myogenic potentials in contradiction to the classical assumption of normal vestibular function. The surprising lack of consistent genotypic to vestibular phenotypic findings as well as no clear vestibular phenotypic patterns among atypical USH cases, indicate that even rigorous vestibular phenotyping data will not reliably differentiate the three USH types.

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Usher’s Syndrome Type II: A Comparative Study of Genetic Mutations and Vestibular System Evaluation

Cited by 19 publications

References 41 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

Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families

Vestibular phenotype‐genotype correlation in a cohort of 90 patients with Usher syndrome

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