[Why do mutations cause disease--a protein chemical perspective].
BACKGROUND
Mutations are of fundamental importance for genetic diversity and evolution, but are also associated with diseases and death. Genetic polymorphisms are common even among healthy individuals and somatic mutations develop in large numbers throughout life. Although most mutations are classified as silent, others may be fatal. No universal procedures exist for the prediction of mutation phenotype.


METHODS
As the main function of DNA is to code for proteins, it is logical to examine the impact of mutations on protein structure and function. On the basis of available databases and our own studies on mutations, protein structure and disease, we present a brief overview of their relationship. The phenylketonuria-associated mutations in human phenylalanine hydroxylase are discussed in more detail, as phenylketonuria is often considered a model system for other inherited metabolic diseases.


CONCLUSIONS
We argue that studies of the kinetic and thermodynamic stability of proteins are important in order to understand the effects of many mutations, and we describe such studies. Knowledge about native, denatured and aggregated forms of proteins is essential to the understanding of how mutations can affect protein stability. We conclude that much of our knowledge in this area is still rudimentary, but we expect that this field of research will evolve rapidly over the next few years.
Kleppe
R
R
Institutt for biokjemi og molekylaerbiologi Universitetet i Bergen Arstadveien 19 5009 Bergen.
Knappskog
P M
PM
Haavik
J
J
D000595:Amino Acid Sequence; D004247:DNA / Q000235:genetics; D016208:Databases, Factual; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011487:Protein Conformation; D011489:Protein Denaturation / Q000235:genetics; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
D004247:DNA