Fragile X Syndrome: New Hopes for the Treatment of a Genetic Disorder

Fragile X syndrome is a genetic disorder caused by a mutation in a gene located at the tip of the X chromosome. It is associated with autism spectrum disorders.

People with fragile X experience a range of symptoms including mental retardation, developmental and speech delays and hyperactivity. They may have certain physical characteristics such as large ears and foreheads, soft muscles and poor coordination.

Together with our colleagues Jonathan Watts and Elizabeth Berry-Kravis, we are a team of scientists with expertise in molecular biology, nucleic acid chemistry and child neurology.

We recently discovered that the mutated gene responsible for fragile X syndrome is active in many people with the disorder, not silenced as previously thought.

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But the affected gene on the X chromosome is still unable to produce the protein it codes for because the genetic material is not properly processed. Correcting this programming error suggests that a potential treatment for fragile X syndrome may one day be available.

Correcting faulty RNA splicing

The FMR1 gene encodes a protein that regulates protein synthesis. Deficiency of this protein leads to excess protein synthesis in the brain leading to many fragile X syndromes.

A mutation that causes fragile X results in extra copies of a DNA sequence called a CGG duplication. Everyone has a CGG repeat in the FMR1 gene, but usually less than 55 copies. Having 200 or more CGG repeats silences the FMR1 gene and causes fragile X syndrome.

However, we found that about 70% of people with fragile X still have a functional FMR1 gene that their cellular machinery can read. But it is altered enough that it cannot direct the cell to produce the protein it encodes.

Genes are transcribed into another type of gene called RNA that cells use to make proteins. Normally, genes are processed before transcription to make a readable strand of RNA. This involves removing non-coding sequences that interfere with the gene and splicing the genetic material back together.

In fragile X individuals, the cellular machinery that makes this cut incorrectly splices the genetic material, so that the protein the FMR1 gene codes for is not produced.

Using cell cultures in the lab, we found that correcting this missplice can restore proper RNA function and produce the FMR1 gene protein. We did this by using short pieces of DNA called antisense oligonucleotides, or ASOs.

When these genetic particles bind to RNA molecules, they change the way the cell is able to read them. That can have effects that can make the cell’s proteins more efficient.

ASOs have been used with remarkable success to treat other childhood disorders, such as spinal muscular atrophy, and are now being used to treat a variety of neurological diseases.

Except for rodent models

Notably, fragile X syndrome is often studied using mouse models. However, because these mice have been genetically engineered to lack a functional FMR1 gene, they are very different from fragile X individuals. In humans, it is not the missing gene that causes fragile X but mutations that lead to the existing gene to lose its function.

Since the fragile X mouse model lacks the FMR1 gene, the RNA is not made and therefore cannot be missed. Our findings would not have been possible using mice.

With further research, future studies in humans may one day inject ASOs into the cerebrospinal fluid of fragile X patients, where they will travel to the brain and hope to restore the proper function of the FMR1 gene and improve their cognitive function.Conversation

Joel Richter, Professor of Neuroscience, UMass Chan Medical School and Sneha Shah, Assistant Professor of Molecular Medicine, Mass Chan Medical School

This article is republished from The Conversation under a Creative Commons license. Read the first article.

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