A meta‐analysis of nonsense mutations causing human genetic disease

@article{Mort2008AMO,
  title={A meta‐analysis of nonsense mutations causing human genetic disease},
  author={Matthew E. Mort and Dobril K. Ivanov and David N. Cooper and Nadia A. Chuzhanova},
  journal={Human Mutation},
  year={2008},
  volume={29},
  url={https://api.semanticscholar.org/CorpusID:205918343}
}
The proportion of disease‐causing nonsense mutations predicted to elicit nonsense‐mediated mRNA decay (NMD) is significantly higher than among nonobserved (potential) nonsense mutations, implying that nonsense mutations that elicit NMD are more likely to come to clinical attention.
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420 Citations

Nonsense Mutations Causing Inherited Diseases: Therapeutic Approaches

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There is an increasing need for sequence-specific repair approaches that are safer and adaptable to personalized medicine that will soon be tested in clinical trials as nonsense therapies, even if they still have some limitations and challenges to overcome.

Serum starvation enhances nonsense mutation readthrough

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Human gene mutation in inherited disease: Molecular mechanisms and clinical consequences

Optimized approach for the identification of highly efficient correctors of nonsense mutations in human diseases

A screening system based on an NMD-prone mRNA should be suitable for identifying molecules capable of efficiently rescuing the expression of human genes harboring a nonsense mutation, and should favor the discovery of candidate drugs for treating genetic diseases caused by nonsense mutations.

Nonsense suppression therapies in human genetic diseases

The mechanisms of PTC readthrough and their regulation are reviewed, as well as the recent advances in the development of novel approaches for PTC suppression, and their role in personalized medicine are reviewed.

Strategies to Correct Nonsense Mutations

A Genome-wide Survey of the Prevalence and Evolutionary Forces Acting on Human Nonsense Snps

A large-scale experimental survey of nonsense SNPs in the human genome is carried out by genotyping 805 of them and a few showed signs of being possibly advantageous, as indicated by unusually high levels of population differentiation, long haplotypes, and/or high frequencies of derived alleles.

Pathologies Susceptible to be Targeted for Nonsense Mutation Therapies

Allele-Specific Prevention of Nonsense-Mediated Decay in Cystic Fibrosis Using Homology-Independent Genome Editing

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42 References

Human Gene Mutation Database (HGMD®): 2003 update

Since its inception, HGMD has been expanded to include cDNA reference sequences for more than 87% of listed genes, splice junction sequences, disease‐associated and functional polymorphisms, as well as links to data present in publicly available online locus‐specific mutation databases.

CpG/CpNpG motifs in the coding region are preferred sites for mutagenesis in the breast cancer susceptibility genes

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The spectrum of single-base-pair substitutions logged in The Human Gene Mutation Database, comprising 7,271 different lesions in the coding regions of 547 different human genes, was analyzed for nearest-neighbor effects on relative mutation rates, suggesting either inefficient DNA replication in regions of high stability or the transient stabilization of misaligned intermediates.

Nonsense mutations in the human β-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation

Findings suggest that nonsense-mediated mRNA decay is not exclusively dependent on the localization of mutations relative to the 3'-most intron, and that other factors may also contribute to determine the cytoplasmic nonsense-mutated mRNA level in erythroid cells.

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations

It is reported that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype, PCWH, is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway.

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Functional analyses of these mRNAs with 5′-proximal nonsense mutations demonstrate that their relative resistance to NMD does not reflect abnormal RNA splicing or translation re-initiation and is independent of promoter identity and erythroid specificity.

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Does the nonsense‐mediated mRNA decay mechanism prevent the synthesis of truncated BRCA1, CHK2, and p53 proteins?

This study investigated whether endogenous alleles of breast cancer predisposing genes carrying nonsense codons were able to produce detectable amounts of truncated proteins in lymphoblastoid cell lines, and found that BRCA1 and CHK2 truncation proteins could not be detected, even when NMD was inhibited.

Evidence that translation reinitiation abrogates nonsense‐mediated mRNA decay in mammalian cells

Evidence is provided that a nonsense codon at position 1, 2 or 10 reduces the abundance of nucleus‐associated TPI mRNA to an average of only 84% of normal because translation reinitiates at the methionine codonat position 14, lending credence to the concept that the nonsense‐mediated reduction in the half‐life of nucleus-associated T PI mRNA involves cytoplasmic ribosomes.

Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease

The physiological role of this surveillance pathway, its implications for human diseases, and why knowledge of NMD is important to an understanding of genotype–phenotype correlations in various genetic disorders are reviewed.