Molecular Mechanisms Underlying Pathogenic Missense Mutations


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.



Aguzzi A and O'Connor T (2010) Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nature Reviews Drug Discovery 9(3): 237–248.

Alberts B, Bray D, Lewis J et al. (1994) Molecular Biology of the Cell, 3rd edn. New York, NY: Garland Science.

Alexov E (2004) Numerical calculations of the pH of maximal protein stability. European Journal of Biochemistry 271(1): 173–185.

Alexov E and Sternberg M (2013) Understanding molecular effects of naturally occurring genetic differences. Journal of Molecular Biology 425(21): 3911.

Anno S, Abe T and Yamamoto T (2008) Interactions between SNP alleles at multiple loci contribute to skin color differences between caucasoid and mongoloid subjects. International Journal of Biological Sciences 4(2): 81.

Ashida A, Yamamoto D, Nakakura H et al. (2012) Molecular effect of a novel missense mutation, L266V, on function of ClC‐5 protein in a Japanese patient with Dent's disease. Clinical Nephrology 82(7): 58–61.

Bauer‐Mehren A (2013) Integration of genomic information with biological networks using cytoscape. Methods in Molecular Biology 1021: 37–61.

Boccuto L, Aoki K, Flanagan‐Steet H et al. (2014) A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation. Human Molecular Genetics 23(2): 418–433.

Buiting K (2010) Prader–Willi syndrome and Angelman syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 154(3): 365–376.

Byun‐McKay SA and Geeta R (2007) Protein subcellular relocalization: a new perspective on the origin of novel genes. Trends in Ecology & Evolution 22(7): 338–344.

Chen R, Mias GI, Li‐Pook‐Than J et al. (2012) Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell 148(6): 1293–1307.

Cong P, Ye Y, Wang Y et al. (2012) A large deletion/insertion‐induced frameshift mutation of the androgen receptor gene in a family with a familial complete androgen insensitivity syndrome. Gene 500(2): 220–223.

Dolzhanskaya N, Gonzalez MA, Sperziani F et al. (2013) A novel p. Leu (381) Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease. Journal of Alzheimer's Disease 39(1): 23–27.

Feuk L, Carson AR and Scherer SW (2006) Structural variation in the human genome. Nature Reviews Genetics 7(2): 85–97.

Forget BG and Bunn HF (2013) Classification of the disorders of hemoglobin. Cold Spring Harbor Perspectives in Medicine 3(2): a011684.

de Gruijter JM, Lao O, Vermeulen M et al. (2011) Contrasting signals of positive selection in genes involved in human skin‐color variation from tests based on SNP scans and resequencing. Investigative Genetics 2: 1–12.

Halldórsson BV and Sharan R (2013) Network‐based interpretation of genomic variation data. Journal of Molecular Biology 425(21): 3964–3969.

Haraksingh RR, Abyzov A, Gerstein M, Urban AE and Snyder M (2011) Genome‐wide mapping of copy number variation in humans: comparative analysis of high resolution array platforms. PLoS One 6(11): e27859.

Haraksingh RR and Snyder MP (2013) Impacts of variation in the human genome on gene regulation. Journal of Molecular Biology 425(21): 3970–3977.

Hecht M, Bromberg Y and Rost B (2013) News from the protein mutability landscape. Journal of Molecular Biology 425(21): 3937–3948.

Hoffmann TJ, Zhan Y, Kvale MN et al. (2011) Design and coverage of high throughput genotyping arrays optimized for individuals of East Asian, African American, and Latino race/ethnicity using imputation and a novel hybrid SNP selection algorithm. Genomics 98(6): 422–430.

Hung M‐C and Link W (2011) Protein localization in disease and therapy. Journal of Cell Science 124(20): 3381–3392.

Kastelic V and Drobnič K (2012) A single‐nucleotide polymorphism (SNP) multiplex system: the association of five SNPs with human eye and hair color in the Slovenian population and comparison using a Bayesian network and logistic regression model. Croatian Medical Journal 53(5): 401–408.

Kim H‐W, Shen T‐J, Sun DP et al. (1994) Restoring allosterism with compensatory mutations in hemoglobin. Proceedings of the National Academy of Sciences of the USA 91(24): 11547–11551.

Kundrotas PJ and Alexov E (2006) Electrostatic properties of protein–protein complexes. Biophysical Journal 91(5): 1724–1736.

Lam HYK, Pan C, Clark MJ et al. (2012) Detecting and annotating genetic variations using the HugeSeq pipeline. Nature Biotechnology 30(3): 226–229.

Laurila K and Vihinen M (2009) Prediction of disease‐related mutations affecting protein localization. BMC Genomics 10(1): 122.

Lobo I (2008) Copy number variation and genetic disease. Nature Education 1(1): 65.

Lofts FJ and Gullick WJ (1992) c‐erbB2 amplification and overexpression in human tumors. Cancer Treatment and Research 61: 161–179.

Marszałek‐Kruk BA, Wójcicki P, Śmigiel R and Trzeciak WH (2012) Novel insertion in exon 5 of the TCOF1 gene in twin sisters with Treacher Collins syndrome. Journal of Applied Genetics 53(3): 279–282.

Nishi H, Tyagi M, Teng S et al. (2013) Cancer missense mutations alter binding properties of proteins and their interaction networks. PloS One 8(6): e66273.

Nussbaum R, McInnes RR and Willard HF (2007) Thompson & Thompson Genetics in Medicine. Philadelphia: W.B. Saunders.

Pentchev K, Ono K, Herwig R, Ideker T and Kamburov A (2010) Evidence mining and novelty assessment of protein–protein interactions with the ConsensusPathDB plugin for Cytoscape. Bioinformatics 26(21): 2796–2797.

Petsko GA and Ringe D (2004) Protein Structure and Function. London: New Science Press.

Shanske AL, Yachelevich N, Ala‐Kokko L, Leonard J and Levy B (2010) Wolf–Hirschhorn syndrome and ectrodactyly: new findings and a review of the literature. American Journal of Medical Genetics Part A 152(1): 203–208.

Sigala PA, Fafarman AT, Schwans JP et al. (2013) Quantitative dissection of hydrogen bond‐mediated proton transfer in the ketosteroid isomerase active site. Proceedings of the National Academy of Sciences of the USA 110(28): E2552–E2561.

Srivas R, Hannum G, Ruscheinski J et al. (2011) Assembling global maps of cellular function through integrative analysis of physical and genetic networks. Nature Protocols 6(9): 1308–1323.

Stefl S, Nishi H, Petukh M, Panchenko AR and Alexov E (2013) Molecular mechanisms of disease‐causing missense mutations. Journal of Molecular Biology 425(21): 3919–3936.

Szöllösi J, Balázs M, Feuerstein BG, Benz CC and Waldman FM (1995) ERBB‐2 (HER2/neu) gene copy number, p185HER‐2 overexpression, and intratumor heterogeneity in human breast cancer. Cancer Research 55(22): 5400–5407.

Takano K, Liu D, Tarpey P et al. (2012) An X‐linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity. Human Molecular Genetics 21(20): 4497–4507.

Talley K and Alexov E (2010) On the pH‐optimum of activity and stability of proteins. Proteins: Structure, Function, and Bioinformatics 78(12): 2699–2706.

Teng S, Madej T, Panchenko A and Alexov E (2009) Modeling effects of human single nucleotide polymorphisms on protein−protein interactions. Biophysical Journal 96(6): 2178–2188.

Teng S, Michonova‐Alexova E and Alexov E (2008) Approaches and resources for prediction of the effects of non‐synonymous single nucleotide polymorphism on protein function and interactions. Current Pharmaceutical Biotechnology 9(2): 123–133.

Witham S, Takano K, Schwartz C and Alexov E (2011) A missense mutation in CLIC2 associated with intellectual disability is predicted by in silico modeling to affect protein stability and dynamics. Proteins: Structure, Function, and Bioinformatics 79(8): 2444–2454.

Yates CM and Sternberg MJE (2013) The effects of non‐synonymous single nucleotide polymorphisms (nsSNPs) on protein–protein interactions. Journal of Molecular Biology 425(21): 3949–3963.

Zhang Z, Miteva MA, Wang L and Alexov E (2012a) Analyzing effects of naturally occurring missense mutations. Computational and Mathematical Methods in Medicine 10(17): 1–15.

Zhang Z, Norris J, Kalscheuer V et al. (2013a) A Y328C missense mutation in spermine synthase causes a mild form of Snyder–Robinson syndrome. Human Molecular Genetics 22(18): 3789–3797.

Zhang Z, Norris J, Schwartz C and Alexov E (2011) In silico and in vitro investigations of the mutability of disease‐causing missense mutation sites in spermine synthase. PLoS One 6(5): e20373.

Zhang Z, Teng S, Wang L, Schwartz CE and Alexov E (2010) Computational analysis of missense mutations causing Snyder–Robinson syndrome. Human Mutation 31(9): 1043–1049.

Zhang Z, Wang L, Gao Y et al. (2012b) Predicting folding free energy changes upon single point mutations. Bioinformatics 28(5): 664–671.

Zhang Z, Witham S, Petukh M et al. (2013b) A rational free energy‐based approach to understanding and targeting disease‐causing missense mutations. Journal of the American Medical Informatics Association 20(4): 643–651.

Further Reading

Castellana S and Mazza T (2013) Congruency in the prediction of pathogenic missense mutations: state‐of‐the‐art web‐based tools. Briefings in Bioinformatics 14(4): 448–459.

Claes K, Poppe B, Machackova E et al. (2003) Differentiating pathogenic mutations from polymorphic alterations in the splice sites of BRCA1 and BRCA2. Genes, Chromosomes and Cancer 37(3): 314–320.

Hacker JH and Kaper J (eds) (2002) Pathogenicity Islands and the Evolution of Pathogenic Microbes, vol. 1, pp. 1–212. Germany: Springer‐Verlag.

Maiti B (2010) Molecular Pathogenesis of Select Mutations in DMD and SEPN1, pp. 1–117. Utah: Department of Human Genetics, University of Utah.

Mullan M, Crawford F, Axelman K et al. (1992) A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid. Nature Genetics 1(5): 345–347.

Valon CL (2007) New Developments in Mutation Research. New York, NY: Nova Publishers.

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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. [doi: 10.1002/9780470015902.a0025698]