Definition: A mutation can now be defined as a permanent change in the DNA. Mutations that affect germ cells are transmitted to the progeny and may give rise to inherited diseases (germline mutations). Mutations that arise in somatic cells understandably do not cause hereditary diseases but are important in the genesis of cancers and some congenital malformations (somatic mutations).

Types

 missense mutations
 frameshift mutations
 splice site mutations
 loss-of-function mutations
 gain-of-function mutations

Effects of protein mutations

 haploinsufficiency
 protein loss of function
 protein truncation
 aminoacid substitution

According to the function of mutated protein

 intracellular accumulation
 lack of transport to cell membrane

 anomalies of glycosylation

See also

 deleterious mutations

• disease-causing mutations
• disease-predisposing mutations

 protective mutations
 mutations datation
 mutations in a gene causing different disorders
 mutation mechanisms
 synonymous mutations

Pathology

 disease-predisposing mutations (genetic predisposition)
 disease-causing mutations (genetic diseases)

Pathogenesis

 Mutations can cause either the deficiency or the inactivity of a protein.

 Many diseases arise from mutations that primarily affect neither expression nor function, but result in a protein with decreased conformational stability.

This conformational instability can intermittently cause the affected protein to unfold and then undergo intermolecular linkage, which results in intracellular aggregation that causes cumulative cell damage.

The insidious nature of protein accumulation explains why some familial diseases characteristically affect individuals in middle- or old-age.

The aggregation of conformationally destabilized proteins is now known to be a feature of many of the neurodegenerative diseases, notably of Alzheimer and Parkinson diseases and the spongiform encephalopathies. (see serpins, serpin family of protease inhibitors).

The common consequence of the mutations in all these diseases is the molecular instability of the encoded protein, which results in the formation of intermolecular beta-linkages, in which single peptide strands become aligned to form highly stable beta-sheets. These beta-linked structures then accumulate to cause cell death and hence disease.

References

 Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002 Oct;3(10):759-68. PMID: #12360234#

 Marnett LJ, Plastaras JP. Endogenous DNA damage and mutation. Trends Genet. 2001 Apr;17(4):214-21. PMID: #11275327#

 Crow JF. The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet. 2000 Oct;1(1):40-7. PMID: #11262873#

 Antonarakis, S. E. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum. Mutat. 11: 1-3, 1998. PubMed ID : #9450896#