The chromosomal instability resulting from this trinucleotide expansion presents clinically as intellectual disability, distinctive facial features, and macroorchidism in males.
[6] The discovery that trinucleotide repeats could expand during intergenerational transmission and could cause disease was the first evidence that not all disease-causing mutations are stably transmitted from parent to offspring.
[citation needed] However, the frequency of occurrence of any one particular repeat sequence disorder varies greatly by ethnic group and geographic location.
[citation needed] Some carriers, during the formation of eggs or sperm, may give rise to higher levels of repetition of the repeat they carry.
There is often increased methylation at CpG islands near the repeat region, resulting in a closed chromatin state, causing gene downregulation.
In this second type of disorder, large repeat expansions in DNA are transcribed into pathogenic RNAs that form nuclear RNA foci.
This, in turn, causes multiple RNA processing defects that lead to the diverse clinical manifestations of these diseases.
First, there may be translation initiated at the usual AUG or a similar (CUG, GUG, UUG, or ACG) start codon.
The second category, toxic RNAs, has repeats located in introns or in a 3' untranslated region of code beyond the stop codon.
The third category, largely producing toxic proteins with polyalanines or polyglutamines, has trinucleotide repeats that occur in the exons of the affected genes.
Except for the CAG repeat expansion in the 5' UTR of PPP2R2B in SCA12, the expanded CAG repeats are translated into an uninterrupted sequence of glutamine residues, forming a polyQ tract, and the accumulation of polyQ proteins damages key cellular functions such as the ubiquitin-proteasome system.
A common symptom of polyQ diseases is the progressive degeneration of nerve cells, usually affecting people later in life.
In some of these diseases, such as Fragile X syndrome, the pathology is caused by lack of the normal function of the protein encoded by the affected gene.
[20] Trinucleotide repeat disorders generally show genetic anticipation: their severity increases with each successive generation that inherits them.
[21] However, that parent's offspring would be at an increased risk of developing Huntington's compared to the general population, as it would take only the addition of one more CAG codon to cause the production of mHTT (mutant HTT), the protein responsible for disease.