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.
Dalšími specifiky těchto onemocnění je homogenita mutací (naprostá většina mutací je typu amplifikací, klasické mutace se u těchto chorob vyskytují jen výjimečně), somatická variabilita v počtu opakování trinukleotidů v různých tkáních, nejsou známy nové mutace, tj. vznik plné mutace (velkého počtu opakování) je vždy postupný – jedná se o familiární choroby, závažnost onemocnění závisí na počtu opakování.
Mezi nejznámější onemocnění spojené s dynamickou mutací patří mutace fragilního X (syndrom Martin-Bellové), Huntingtonova chorea, myotonická dystrofie a Friedreichova ataxie.
Existují dvě skupiny dynamických mutací:
- Mutace s amplifikací v nekodující – netranslatované oblasti genu (promotoru, intronu) vede ke změně exprese genu, jako je tomu u syndromu fragilního X (amplifikován triplet CGG v 5´netranslatované oblasti genu FMR1 = Fragile X Mental Retardation 1), u myotonické dystrofie (amplifikován triplet CTG v 3´ netranslatované oblasti genu pro proteinkinázu DMPK) a u Friedreichovy ataxie (amplifikován triplet AAG v intronu genu pro mitochondriální protein frataxin)
- Amplifikace v exonu (obvykle triplet CAG) neovlivní transkripci genu, ale vzniklý protein je abnormální (obsahuje polyglutaminový trakt). To je známo u Huntingtonovy choroby (protein huntingtin) a u některých dalších progresivních neurodegenerativních onemocnění (tzv. polyglutaminové poruchy).
Syndrom fragilního X
