https://www.pulsus.

com/scholarly-articles/trinucleotide-repeat-diseases--antecipation-
diseases.pdf?
fbclid=IwAR3otvAZx_15ObNazcLCHU7eXF6fvTk63VyxzG5s9i5_qnh2RLHRdQ4K8HY
General mechanism and why it cause diseases in
human:
Nucleotide repeat expansion generally affects on the process from DNA to protein through
transcription and translation.

Depending on the location or length of nucleotide repeat ( coding or non-coding region,... ),

the level of gene expression and type of diseases are performed.
There are two main types of triplet repeats diseases.
The first type is that the expanded triplet repeat disorders is translated, usually including
poly-glutamine or poly-alanine homorepeats.
In the second type, triplet repeats which are present in non-coding regions of the gene can
be expressed at the mRNA level (affecting expression levels of coded proteins) but are not
translated, so it have no effect on protein structure. However, the produced mRNA
sometimes give rise to highly repetitive peptides of different length and amino acid content
by translating. The formation of a toxic homopolypeptide might be derive from this step
which can lead to the development of the pathology
DM1,2
https://www.ncbi.nlm.nih.gov/pubmed/16876389
https://www.ncbi.nlm.nih.gov/pubmed/19909263
https://www.sciencedirect.com/science/article/pii/S0925443906000986?via%3Dihub

Myotonic Dystrophy or DM is a dominantly complex inherited genetic disorder that is the

most common cause of muscular dystrophy in adults.
There are 2 different forms of diseases which are caused by different microsatellite
expansions in 2 loci:
Myotonic dystrophy type 1 or DM is caused on chromosome 19 which contain an expansion
of a CTG repeat located in the 3' untranslated region of DMPK (myotonic dystrophy protein
kinase)
Myotonic dystrophy type 2 or DM2 is caused by an unstable CCTG repeat in intron 1 of
ZNF9 (zinc finger protein 9) on chromosome 3 .
And both of similiar features that DM1 and DM2 having is that they are caused by a repeat
expansion in a region transcribed into RNA but not translated into protein. The mutant RNA
transcripts of DM1 and DM2 aberrantly affect the splicing of the same target RNAs, such as
chloride channel 1 (ClC-1) and insulin receptor (INSR), resulting in their shared myotonia
and insulin resistance.
The pathogenic mechanism of Myotonic Dystrophy involves the RNA transcribed from the
expanded allele containing long tracts of (CUG)(n) or (CCUG)(n). The toxic effect of RNA
through two RNA-binding proteins is MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-
binding protein 1) which is relevant to other RNA dominant disorders.
In specific, RNA transcripts likely form double-stranded hairpin structures from the extended
tracts of CUG or CCUG repeats, to which MBNL proteins prefer to bind. MBNL proteins co-
localize with the ribonuclear inclusions formed by mutant RNA but the nuclear sequestration
of MBNL which directly leads to a significant decrease in normal MBNL activity, or whether
expanded CUG/CCUG RNA signals an alternate pathway to MBNL functional inhibition is
unclear. CUG-BP1 levels are increased in DM1 cells, independent of MBNL protein
regulation and increased CUG-BP activity and/or loss of MBNL function may lead to aberrant
gene splicing events associated with DM1 and DM2 as shown.
FXTAS
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418347/

Fragile X-associated tremor/ataxia syndrome (FXTAS) which are caused by a CGG triplet
repeat expansion within the 5′ UTR of FMR1 is a neurodegenerative disorder . Normally,
individuals who possess between 5 and 54 CGG repeats, and full mutation CGG repeats
greater than 200 can have the neurodevelopmental disease fragile X syndrome (FXS).
Therefore, the FXS lead the owner to the excessive methylation of FMR1 and loss of FMRP
protein. Moreover, the individuals with 55–200 CGG repeats are referred to as premutation
carriers.
RNA toxicity and repeat associated non-AUG translation (RAN) protein toxicity (via RAN) are
two widely accepted mechanisms for the pathogenesis of FXTAS.
There are several evidences relate to the RNA toxicity mechanism.

First, older adults do not develop FXTAS, who do not express FMR1 mRNA and lack FMRP,
are full of the mutation ( >200 repeats)

Second, in FXTAS, formation of nuclear RNA aggregates since the significant upregulation
(2–8 fold) of the expanded CGG-repeat FMR1 mRNA which bind with proteins to prevent
them from performing their normal biological functions, such as mRNA transcription and
splicing, as well as dendritic mRNA transport. The level of FMR1 protein in cells from
premutation carriers, however, remains relatively unaltered.

Third, besides the RNA-binding proteins (RBPs), these inclusions which contain proteins do
not bind to CGG-repeat on mRNA and are reminiscent of the neuronal intranuclear
inclusions founding in protein-mediated neurodegenerative disorders and polyglutamine
diseases. Therefore, a protein-driven mechanism of FXTAS pathogenesis was uncovered, in
which the premutation CGG repeat expansion was found to induce RAN translation within
the 5′ UTR of FMR1 mRNA via an AUG-independent mechanism. The resulting polyglycine-
containing protein, FMRpolyG, is present in the brains of FXTAS patients and was found to
be toxic to human cell lines.