Nonsense Mutation Correction in Human Diseases: An Approach for Targeted Medicine provides an introduction on genetic diseases, discusses the prevalence of nonsense mutations, the consequences of a nonsense mutation for the expression of the mutant gene, and the presentation of the nonsense-mediated mRNA decay (NMD).

It presents the mechanism of action and rationale associated with each strategy to correct nonsense mutations with the results of clinical trials to further support this basis. In addition, the book shows how it may be possible to combine several of these strategies to ultimately improve the efficiency of correction, also suggesting the future goals and objectives to improve treatment modalities in this evolving sphere of personalized medicine.

Features basic biological and clinical constructs that inform the application of genomic data to clinical decision-making
Includes theories and methods that can be used to link bio-molecular and clinical phenotypes so as to enable integrative hypothesis discovery, testing, and downstream evidence-based practice
Provides design patterns and use cases that contextualize the clinical decision-making and evidence-based practice relative to real world requirements and stakeholders

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Yes, you can access Nonsense Mutation Correction in Human Diseases by Fabrice Lejeune,Hana Benhabiles,Jieshuang Jia in PDF and/or ePUB format, as well as other popular books in Biological Sciences & Genetics & Genomics. We have over one million books available in our catalogue for you to explore.

Information

Publisher

Academic Press

Year

2016

ISBN

9780128044698

Topic

Biological Sciences

Subtopic

Genetics & Genomics

Index

Biological Sciences

Chapter 1

General Aspects Related to Nonsense Mutations

Abstract

Genetic diseases are caused by mutations on the DNA molecule. These mutations can affect the peptidic sequence of the protein, or some regulator elements involved during the gene expression, or some quality controls mechanisms. Nonsense mutations change a coding codon into a noncoding codon or STOP/nonsense codon. The consequence of a premature termination codon (PTC) is the accelerated decay of the mRNA harboring the PTC, by a mechanism called nonsense-mediated mRNA decay (NMD). NMD occurs in the cytoplasm after pre-mRNA splicing, and export. For some aspects, NMD is tightly linked to pre-mRNA splicing, a key maturation step of mRNAs. In this chapter, pre-mRNA splicing and NMD mechanisms will be described, in order to understand the existing interactions between them. In particular, their regulation and the proteins involved in these processings will be tackled.

Keywords

pre-mRNA splicing

nonsense-mediated mRNA decay

premature termination codon

alternative splicing

exon junction complex

NMD regulation

Contents

1 Premature Termination Codon, Nonsense Mutation, and Consequences on Gene Expression 2

2 Pre-mRNA Splicing Mechanism 7

2.1 Generalities 7

2.2 Categories of Alternative Splicing 12

2.3 Regulation of Splicing 14

2.4 Pathologies Associated with Splicing Defaults 16

3 Nonsense-Mediated mRNA Decay (NMD) Mechanism 20

3.1 Generalities 20

3.2 Main Proteins Involved in NMD 23

3.3 EJC-Dependent Model 37

3.4 Model Involving the Distance Between the Stop Codon and the Position of the Poly(A) Binding Protein C1 44

3.5 Natural Substrates of NMD 51

3.6 Regulation 55

3.7 UPF2, UPF3X/UPF3b Independent Pathway 58

3.8 Pathologies Associated with NMD Defaults 59

4 Correction of Nonsense Mutations, a Case of Targeted Therapy 61

References 62

DNA is the carrier molecule of the genetic information, and has to pass it on the daughter cells in respect of this information. Any modifications in the DNA molecule between two cell generations will result into a mutation. Besides maintaining the DNA molecule’s integrity in order to preserve the genetic message, gene expression also has to reflect the encoded information carried by the DNA molecule and be delivered in an accurate way according to external and internal stimuli. To ensure this accuracy of the gene expression, quality controls are present for...

Cover
Title page
Table of Contents
Copyright
About the Authors
Acknowledgments
Chapter 1: General Aspects Related to Nonsense Mutations
Chapter 2: Pathologies Susceptible to be Targeted for Nonsense Mutation Therapies
Chapter 3: Strategies to Correct Nonsense Mutations
Chapter 4: Conclusions
Glossary
Subject Index