The work, which identified mutations associated with eased Rett symptoms in mice, was the first to point out the involvement of DNA damage response in this disease.
The findings may help scientists understand the underlying mechanisms of Rett syndrome, identify genetic modifiers of disease severity, and reveal potential therapeutic targets.
Still, future studies are needed to confirm the therapeutic potential of these genes in Rett, researchers said.
The study, “Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology,” was published in the journal Genome Research.
Almost all cases of Rett syndrome are caused by mutations in the MECP2 gene located on the X chromosome. Since women have two X chromosomes, mutations in one MECP2 gene copy are partially compensated by a healthy copy in the other chromosome, while in males — who have only one X chromosome — MECP2 mutations usually are deadly before birth.
MECP2 contains the instructions to produce MeCP2, a protein that regulates the activity of other genes — switching them on or off — by changing chromatin, the DNA-protein complex that packages DNA into chromosomes inside a cell nucleus.
MeCP2 is known to play a critical role in brain development and function, being involved in the growth of nerve cells and in maintaining synapses (the junctions between nerve cells where messages are transmitted). However, many of its functions and systemic effects remain poorly understood.
The identification of genes affected by MECP2 mutations and genes whose mutations lessen the severity of Rett symptoms would help to clarify the mechanisms behind the disease and open new therapeutic avenues.
Now, a team from Canada, along with colleagues in the U.S., have identified 22 genes in which mutations were associated with less severe disease in a mouse model of Rett syndrome.
Among the male offspring testing positive for MECP2 mutations, the scientists then screened for those with less-severe symptoms and identified the underlying mutation associated with therapeutic benefit.
Results highlighted 22 genes as potential modifiers of Rett’s severity, 63% of which were involved in the suppression of gene activity, chromatin modification, or DNA repair. In addition, most of these genes fell into three major pathways: fat metabolism and homeostasis (balance), synaptic function, and DNA damage response.
Notably, the screen was the first to suggest a role for DNA damage response — including that involved in the repair of double-strand breaks (DBSs) — in Rett’s development.
DBSs, in which both strands of a DNA molecule are cut, occur naturally in nerve cells and are important for normal neuronal development. However, if left unrepaired, DSBs accumulation in the brain leads to neurological disease.
Considering that MECP2’s absence is associated with accumulated genetic damage, the mechanisms involved in DSBs repair may be important to understand Rett syndrome, the team said.
The team also said that many mice showing the greatest reduction in symptom burden carried mutations in more than one modifier gene, suggesting that combination, rather than single, therapies may be more effective for Rett syndrome.
These findings “paint a picture of altered metabolism and DNA damage that modulate synaptic function to cause [disease] in Rett syndrome,” the investigators wrote.
“Modifier screens in model organisms may thus help to identify the multitude of genetic variants that influence human disease presentation, as they may point to therapeutic entry points,” they added.
The team also said, however, that this type of screen has limitations and further studies are needed to confirm the potential of these candidate genes as therapeutic targets for Rett syndrome.
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