Instability of repetitive sequences
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Dynamic mutations
Mutation is defined as a suden, undirected and permanent change in genetic material. However, this characteristic is not met by the type of mutations that we call dynamic mutations. Dynamic mutations are associated with the expansion of an unstable element (mostly a repeated trinucleotide) that is amplified with a gene, either in a coding region (exon) or in a non-coding part, i.e. in a promoter or in an intron. The standart alleles of these genes are polymorphic, i.e. they have a variable, mostly small number of repetitions of a certain triplet. This repeat can be increased during the transmission of the gene from generation to generation to such an extent that it results in a change in gene expression or function of the gene produuct, which is associated with clinical impairment. Amplification (multiplication) is caused by an error during replication, when the repetition of trinucleotides causes inaccuracy in the pairing and the formation of a protrusion of the daughter DNA chain and repeated replication of the segment.
Diseases associated with multiplication of trinucleotide repeats
Syndromes associated with this type of mutation show deviations from the expected mode of transmission, deviations such as anticipation (Sherman's paradox), which means a worsening of sympoms from generation to generation, or a shortening of the onset of the disease in subsequent generations, as well as the dependence of the severity of the disease on parental origin (transmission) mutation. The dependence of trinucleotide expansion on the sex of the transmitting parent has been described in fragile X syndrome and in myotonic dystrophy, when a large increase in amplification occurs during maternal transmission - in fragile X it leads to a change of premutation in a full mutation (associated with disability in sons), in myotonic dystrophy to severe congenital forms of the disease. In Huntington's disease, amplification of the element during paternal transmission leads to an earlier onset of the disease.
Other specifics of these diseases are the homogeneity of mutations (the vast majority of mutations are of the amplification type, classic mutations occur only exceptionally in these diseases), somatic variability in the number of trinucleotide repeats in different tissues, no new mutations are known, i.e. the emergence of a full mutation (a large number of repeats) is always gradual - these are familiar diseases, the severity of the disease depends on the number of repetitions.
The most well-known diseases associated with dynamic mutation include the fragile X mutation (Martin-Bell syndrome), Huntington's chorea, myotonic dystrophy and Friedreich's ataxia.
There are two groups of dynamic mutations:
- A mutation with amplification in the non-coding - untranslated region of the geene (promoter, intron) leads to a change in gene expression, such as in fragile X syndrome (amplified CGG triplet in the 5' untranslated region of the gene FMR1 = Fragile X Mental Retardation 1), in myotonic dystrophy (amplified triplet CTG in the 3' untranslated region of the gene for the protein kinase DMPK) and in Friedreich's ataxia (amplified triplet AAG in the intron of the gene for the mitochondrial protein frataxin)
- Amplification in an exon (usually a CAG triplet) does not affect gene transcription, but the resulting protein is abnormal (containing a polyglutamine tract). This is known in Huntington's disease (huntingtin protein) and in some other progressive neurodegenerative diseases (so-called polyglutamine disorders).
Syndrom fragilního X
