‘Dark genome’ is involved in Rett Syndrome
Researchers at the Epigenetics and Cancer Biology Program at IDIBELL led by Manel Esteller, ICREA researcher and professor of genetics at the University of Barcelona, have described alterations in noncoding long chain RNA sequences (lncRNA) in Rett syndrome.
These molecules act as supervisor agents responsible of ‘switch on’ or ‘switch off’ other genes in our genome that regulate the activity of neurons. The work has been published in the last issue of the journal RNA Biology.
Dark genome
Only 5% of our genetic material are genes that encode proteins. The remaining 95% is known as dark genome or non-coding DNA and its function is still unknown. Part of this DNA produces RNA molecules called noncoding long chain RNA (lncRNAs).
Rett Syndrome
Rett syndrome is a neurodevelopmental disease and it is the second most common cause of mental retardation in females after Down syndrome. Clinical symptoms occur between 6 and 18 months after birth and consist of a loss of cognitive, social and motor capacities accompanied by autistic behaviors, eg, stereotypic hand movements.
Today there is no effective treatment of the disease but the control of their symptoms. The syndrome is usually due to the presence of a mutation in MeCP2 epigenetic gene that, as a magnet, regulates the expression of many other genes of the cell.
Esteller’s team works with a mouse model that faithfully reproduces the characteristics of the human Rett syndrome. In this study, researchers compared the expression of long chains of RNA in healthy and diseased animals and found that the presence of mutations in the Mecp2 gene causes alterations in the activity of lncRNA.
Rett syndrome is a rare, severe, “girls only” form of autism. It’s usually discovered in the first two years of life, and a child’s diagnosis with Rett syndrome can feel overwhelming. Although there’s no cure, early identification and treatment may help girls and families who are affected by Rett syndrome.
Who Gets Rett Syndrome?
Rett syndrome is an autism spectrum disorder that affects girls almost exclusively. It’s rare - only about one in 10,000 to 15,000 girls will develop the condition.
In most cases of Rett syndrome, a child develops normally in early life. Between 6 and 18 months of age, though, changes in the normal patterns of mental and social development begin.
What Are the Symptoms of Rett Syndrome?
Although it’s not always detected, a slowing of head growth is one of the first events in Rett syndrome. Loss of muscle tone is also an initial symptom. Soon, the child loses any purposeful use of her hands. Instead, she habitually wrings or rubs her hands together.
Around 1 to 4 years of age, social and language skills deteriorate in girls with Rett syndrome. She stops talking and develops extreme social anxiety and withdrawal or disinterest in other people.
Rett syndrome also causes problems with muscles and coordination. Walking becomes awkward as girls develop a jerky, stiff-legged gait. A girl with Rett syndrome may also have uncoordinated breathing and seizures.
One such altered lncARN regulates the function of a key neurotransmitter in the nervous system in all vertebrates brain (GABA receptor). “Its alteration”, says Esteller, “could explain the defects of communication between neurons in girls affected by Rett Syndrome.”
According to Manel Esteller “this finding, in addition to increasing knowledge about the causes of the disease, could open the door to new therapeutic strategies that target lncRNA molecules or GABA receptor.”
The study was supported by the Department of Health of the Generalitat de Catalunya, the Catalan Institute of Advanced Studies (ICREA), the Spanish Ministry of Health (E-RARE), the European Project EPINORC DISCHROM and the Fondation Lejeune (France) and the Catalan Association Rett Syndrome.
What causes Rett syndrome?
Nearly all cases of Rett syndrome are caused by a mutation in the methyl CpG binding protein 2, or MECP2 (pronounced meck-pea-two) gene. Scientists identified the gene - which is believed to control the functions of many other genes - in 1999. The MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which is needed for brain development and acts as one of the many biochemical switches that can either increase gene expression or tell other genes when to turn off and stop producing their own unique proteins. Because the MECP2 gene does not function properly in individuals with Rett syndrome, insufficient amounts or structurally abnormal forms of the protein are produced and can cause other genes to be abnormally expressed.
Not everyone who has an MECP2 mutation has Rett syndrome. Scientists have identified mutations in the CDKL5 and FOXG1 genes in individuals who have atypical or congenital Rett syndrome, but they are still learning how those mutations cause the disorder. Scientists believe the remaining cases may be caused by partial gene deletions, mutations in other parts of the MECP2 gene, or additional genes that have not yet been identified, and they continue to look for other causes.
Is Rett syndrome inherited?
Although Rett syndrome is a genetic disorder, less than 1 percent of recorded cases are inherited or passed from one generation to the next. Most cases are spontaneous, which means the mutation occurs randomly. However, in some families of individuals affected by Rett syndrome, there are other female family members who have a mutation of their MECP2 gene but do not show clinical symptoms. These females are known as “asymptomatic female carriers.”
Article reference
Petazzi P., Sandoval J., Szczesna K., Jorge O.C., Roa L., Sayols S., Gomez A., Huertas D. and Esteller M. Dysregulation of the long non-coding RNA transcriptome in a Rett syndrome mouse model. RNA Biology, 10(7), 2013.
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