Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and<i>PEX26</i>mutated in Heimler syndrome

Neuhaus, Christine; Eisenberger, Tobias; Decker, Christian; Nagl, Sandra; Blank, C. A.; Pfister, Markus; Kennerknecht, Ingo; Müller-Hofstede, Cornelie; Issa, Peter Charbel; Heller, Raoul; Beck, Bodo B.; Rüther, Klaus; Mitter, Diana; Rohrschneider, Klaus; Steinhauer, Ute; Korbmacher, Heike; Huhle, Dagmar; Elsayed, Solaf M.; Taha, Hesham M.; Baig, Shahid Mahmood; Stöhr, Heidi; Preising, Markus N.; Markus, Susanne; Moeller, Fabian; Lorenz, Birgit; Nagel-Wolfrum, Kerstin; Khan, Arif O.; Bolz, Hanno J.

doi:10.1002/mgg3.312

Cited by 56 publications

(42 citation statements)

References 119 publications

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“…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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“…Human USH is closely associated with spontaneous mutations in multiple genes [29]. Hitherto, the majority of USH mouse models have been generated by transgenic technology or induced by ethylnitrosourea [30,31].…”

Section: Discussionmentioning

confidence: 99%

A Natural Occurring Mouse Model with Adgrv1 Mutation of Usher Syndrome 2C and Characterization of its Recombinant Inbred Strains

Yan

Long

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Our laboratory discovered a Kunming mouse with enormous electroretinogram (ERG) defects. Its auditory brainstem response (ABR) threshold was significantly elevated and closely resembled the features of Usher syndrome (USH). This study sought to cross these USH-like mice (named KM^ush/ush mice) with CBA/CaJ mice to establish recombinant inbred strains and identify their phenotypes and genotypes. Methods: KM^ush/ush mice were crossed with CBA/CaJ mice to establish inbred strains by sibling mating. ERG, ABR, ocular fundus morphology, histological examinations of the retina and inner ear, quantitative real-time polymerase chain reaction, western blotting, and exon sequencing were performed to assess the phenotypes and genotypes of the offspring strains. Results: The F1 hybrids from crossing KM^ush/ush and CBA/CaJ mice had normal ERG and ABR responses. The F2 offspring from intercrossing the F1 mice showed a segregation of the retinitis pigmentosa (RP) and hearing loss phenotypes. The CBA-1^ush/ush mice had an RP phenotype that was characterized by a vanished ERG waveform and loss of the outer nuclear layer. Their Pde6b gene had a nonsense mutation that resulted in the failure of protein production in western blotting. However, the ABR threshold of this strain of mice was normal. The CBA-2^ush/ush mice had normal retinal function and architecture. Their ABR threshold was increased, with a dramatic degeneration of the stereocilia bundles in the outer hair cells of the inner ear. Whole exome sequencing and exon sequencing revealed a deletion of one base pair in exon 31 of the Adgrv1 gene, which would result in the premature termination of protein encoding. The level of Adgrv1 mRNA was reduced in the CBA-2^ush/ush mice. The CBA-3^ush/ush mice had phenotypes of RP, elevated ABR threshold, and degeneration of the stereocilia bundles in the outer hair cells. They were closely associated with the nonsense mutations of Pde6b and Adgrv1, respectively. Conclusion: We isolated a mouse strain with hearing loss from inbred mice with retinal degeneration and established it as a recombinant inbred strain with a spontaneous mutation in Adgrv1, the human Usher syndrome 2C gene. The retinal degeneration was cause by a mutation in Pde6b, while the hearing loss was caused by a mutation in Adgrv1.

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“…Usher syndrome, caused by a 2 autosomal recessive alleles (USH1 allele results in congenital deafness while USH2 allele results in progressive hearing impairment), is estimated to account for 11% of deafness in children. 16 CNV analysis was performed on next generation sequencing (NGS) data of 138 patients clinically diagnosed with Usher syndrome and found that CNVs were found in 10% of the patients with biallelic USH2A mutations.…”

Section: Intracellular Landscapesmentioning

confidence: 99%

“…Mutational landscape refers to the frequency of mutations and/or type of mutations across a biological entity, 17 which may include CNVs 16,18 and single nucleotide polymorphisms or SNPs. 19 As mutation can be broadly defined as a permanent change in the nucleotide sequence, mutational landscape can be seen as the superset of all measurable nucleotide variations between individuals of the same species or across species.…”

Section: Intracellular Landscapesmentioning

confidence: 99%

Back-of-the-Envelope Guide (A Tutorial) to 10 Intracellular Landscapes

Ling¹

2018

MOJPB

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Copy number landscape 4 often refers to copy number variation (CNV), which is the differences between the numbers of copies of one or more nucleotides within individuals in the same species. The repeats can range from a few bases; such as, polyglutamine repeats; 5 to entire genes; such as alpha-amylase 6 and neutrophil cytosolic factor 1. 7 CNV can be a result when sections of a genome are duplicated/ repeated or deleted; 8,9 which exists in both higher eukaryotes, such as humans, 10 and prokaryotes, such as Escherichia coli; 11 and is implicated in several disease phenotypes. 8 For example, CNV in neutrophil cytosolic factor 1 has been implicated in rheumatoid arthritis 7 and CNV in protease has been implicated in anthropogenic toxins in arthropods 12 as differences in copy number may have an

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Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, andPEX26mutated in Heimler syndrome

Cited by 56 publications

References 119 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

A Natural Occurring Mouse Model with Adgrv1 Mutation of Usher Syndrome 2C and Characterization of its Recombinant Inbred Strains

Back-of-the-Envelope Guide (A Tutorial) to 10 Intracellular Landscapes

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