Nonsense suppression therapies in ocular genetic diseases

Wang, Xia; Gregory‐Evans, Cheryl Y.

doi:10.1007/s00018-015-1843-0

Cited by 21 publications

(17 citation statements)

References 57 publications

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“…Since the first successful report of preimplantation genetic testing [83], this preventive intervention appears promising for future disease management in families at risk for having children with inherited retinoblastoma. With respect to RB1 mutational signature, since nonsense mutations comprise majority of the reported point mutations in RB, as also shown in our study, nonsense suppression therapy which allows readthrough of premature termination codon (PTCs), restoring the protein function [84]; offers possible future targeted therapeutics of such cases. Generation 4 polyamidoamine (G4PAMAM) dendrimers, which act as delivery system of vascular endothelial growth factor antisense oligodeoxynucleotides were recently reported to have antitumor properties, both in vitro and in vivo [85].…”

Section: Discussionmentioning

confidence: 87%

Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

et al. 2017

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Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variantc.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic family members carrying low-penetrance, germline mosaicism or heritable unilateral mutational phenotypes.

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Section: Discussionmentioning

confidence: 87%

Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling

et al. 2017

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“…For example, drugs that promote ribosomal read-through of PTCs could in principle, be used to treat the dominant nonsense mutations Q64X, Q312X, Q341X, and Q344X, a strategy that has been studied for more that 40 different disease genes (Lee and Dougherty, 2012; Wang and Gregory-Evans, 2015) (Guerin et al, 2008). The major challenge of this approach is getting sufficient read-through to affect the disease phenotype.…”

mentioning

confidence: 99%

Nonsense mutations in the rhodopsin gene that give rise to mild phenotypes trigger mRNA degradation in human cells by nonsense-mediated decay

Roman-Sanchez

Wensel

Wilson

2016

Experimental Eye Research

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Eight different nonsense mutations in the human rhodopsin gene cause retinitis pigmentosa (RP), an inherited degenerative disease of the retina that can lead to complete blindness. Although all these nonsense mutations lead to premature termination codons (PTCs) in rhodopsin mRNA, some display dominant inheritance, while others are recessive. Because nonsense-mediated decay (NMD) can degrade mRNAs containing PTCs and modulate the inheritance patterns of genetic diseases, we asked whether any of the nonsense mutations in the rhodopsin gene generated mRNAs that were susceptible to degradation by NMD. We hypothesized that nonsense mutations that caused mild RP phenotypes would trigger NMD, whereas those that did not engage NMD would cause more severe RP phenotypes—presumably due to the toxicity of the truncated protein. To test our hypothesis, we transfected human rhodopsin nonsense mutants into HEK-293T and HT-1080 human cells and measured transcript levels by qRT-PCR. In both cell lines, rhodopsin mutations Q64X and Q344X, which cause severe phenotypes that are dominantly inherited, yielded the same levels of rhodopsin mRNA as wild type. By contrast, rhodopsin mutations W161X and E249X, which cause recessive RP, showed decreased rhodopsin mRNA levels, consistent with NMD. Rhodopsin mutant Y136X, a dominant mutation that causes late-onset RP with a very mild pathology, also gave lower mRNA levels. Treatment of cells with Wortmannin, an inhibitor of NMD, eliminated the degradation of Y136X, W161X, and E249X rhodopsin mRNAs. These results suggest that NMD modulates the severity of RP in patients with nonsense mutations in the rhodopsin gene.

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“…Interaktion mit weiteren Proteinen) im komplexen Gefüge der Zelle wahrzunehmen. Des Weiteren kann ein PTC die Degradation der mRNA über den sogenannten "nonsense-mediated decay" (NMD) induzieren [23]. Diese zelleigene Qualitätskontrolle inhibiert einerseits die potenzielle zytotoxische Wirkung von verkürzten Polypeptiden, führt andererseits aber auch dazu, dass das Template für das potenziell funktionelle Protein degradiert wird.…”

Section: Nonsense-mutationen: Entstehung Und Molekulare Folgeunclassified