Molecular Mechanisms Underlying Pathogenic Missense Mutations

Abstract

Research has identified there is a multiplicity of plausible molecular effects caused by human genetic differences that may lead to human diseases. Although human deoxyribonucleic acid (DNA) variations and rare mutations may be manifested at different levels and different magnitudes, a single nucleotide polymorphism (SNP) to a missing chromosome or a single amino acid mutation to a truncated protein, the pathological effect is the malfunction of the cell or the corresponding organ. It is pointed out that pathological DNA defects can cause more than one phenotypic change to the wild‐type macromolecular characteristics, for example, alterations of macromolecular stability and a variation in the ability to interact with macromolecular partners. The main obstacles to predicting pathogenic DNA variations are the complexity of biological reactions and the difficulty of assessing the threshold of the change that will make it pathogenic. Although some small deviations from the wild‐type properties of a particular biomolecule or a network may be harmless and result in natural differences between individuals, the deviations of the same magnitude occurring in different molecule or network can be pathogenic. These diverse molecular mechanisms that induce the malfunctions are the primary focus of this review.

Key Concepts:

  • Molecular mechanisms of pathogenic mutations refer to the disease‐causing change of the wild‐type properties of the corresponding macromolecules and networks. It could be an effect altering a particular characteristic, for example, stability, but could also be a combination of several factors affecting normal function of the cell.

  • The magnitude of change of the wild‐type characteristics alone cannot be used to predict whether a mutation is pathogenic. In some cases, a small deviation from the wild‐type properties can be deleterious, whereas in others, much larger changes are observed without a disease‐causing effect. Frequently, a detailed knowledge of the biological reactions that are involved is needed to discriminate the pathogenic mutations from harmless variations.

  • Personalised medicine provides personalised or individualized medical care on the basis of an individual's DNA.

  • The knowledge of an individual's DNA is emerging as a powerful tool for selecting the most efficient drug among several alternative drugs available in the market.

  • A DNA defect in a particular gene may not be pathogenic if there is a compensatory mechanism accounting for dysfunctional product and if the dysfunctional product is not toxic for the cell.

Keywords: human DNA variations; single nucleotide polymorphism (SNP); disease‐causing mutations; pathogenic mutations; personalised medicine; personalised diagnostics

Figure 1.

Illustration of different types of mutations at (a) DNA and protein sequence level and (b) chromosomal level.

Figure 2.

Illustration of plausible effects caused by a mutation. From the top to the bottom, change of stability, change of binding affinity and change of subcellular location.

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Wu, Bohua, Eggert, Julia, and Alexov, Emil(Aug 2014) Molecular Mechanisms Underlying Pathogenic Missense Mutations. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025698]