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).
Fragile X syndrome
Template:Infobox - genetic disease
Fragile X Syndrome (Fragile X Chromosome Syndrome, Martinuv-Bell syndrome) is a disease that got its name from a specific chromosomal abnormality -fragility in the subterminal part of the long arms X chromosome (band Xq27.3 – FRAXA), which occurs in a part of cells under special culture conditions (low serum content, reduced folic acid content in the medium).
Pathogenesis
In affected mentally retarded men, there is an amplification of trinucleotide sequences in the promoter of the FMR1 gene located in this region of the X chromosome. CCG / CGG. This mutation arises from a so-called premutation occurring in the mothers of affected men who have this amplification to a lesser extent (50-200 copies). Normal individuals also have some repeats of this sequence, but to a much lesser extent than individuals with the premutation (6–50 copies). The transformation of an unstable premutation into a full mutation (i.e. an increase in the length of the amplificate to more than 200 copies) occurs only during transmission by a woman, no elongation occurs when the element passes through spermiogenesis. A full mutation, i.e. an increase in the trinucleotide repeat above 200 copies leads to methylation of this element, and since it is located in the promoter of the gene, arrest of transcription of the gene occurs and the '"mental retardation"' and other clinical manifestations. It is assumed that amplification of the amplification can occur only in early embryogenesis (but it is determined in gametogenesis), which is evidenced by somatic heterogeneity in the length of the repeat, degree of methylation, and also the existence of individuals - mosaics full of mutation and premutation.
"New mutations" have not been described in this disease, i.e. the emergence of a full mutation in the offspring of a person with a normal number of repeats. The formation of a full mutation always happens by gradually increasing the element through premutation. The length of the repeat sequences correlates with the degree of mental retardation and with cytogenetic expression.
There is an other fragile site (FRAXE) on the X chromosome associated with mild mental retardation.
Clinical signs
- mental retardation,
- elongated face,
- rough features,
- big ears,
- macroorchidism.
