Fragile X
and our research
Our Research
Click here to see what sparks our interest in Fragile X research.
What is Fragile X?
Fragile X Syndrome (FXS) is a condition with a known genetic cause, which can be identified with a simple blood test. Approximately 1 in 250 females and 1 in 600 males are carriers of the Fragile X pre-mutation, which can be passed down to their children with no signs until after birth. Most often carriers of Fragile X pre-mutation have no idea of the condition, in some cases, symptoms may develop in later life, but most often there are no signs of the underlying potential in the carriers genetic makeup.
Fragile X Syndrome is associated with a number of psychological and physical characteristics, it is the most common cause of inherited learning disability in children. Fragile X underlies up to 1 in 20 cases of autism.
How does Fragile X affect people?
Children affected by Fragile X do not produce the FMR Protein which is crucial in the development of the pathways of the brain. The means they often display autistic-like symptoms with high anxiety in social situations. Learning is very difficult and alternative techniques need to be employed to help students at school.
The development of the brain is vital in children, and therefore the effects of Fragile X are life long. Girls usually have milder effects than boys, as a boy have one X and one Y chromosome and girls have two X chromosomes the second X may make up the difference for the damaged X. This is not always the case and some girls present with profound difficulties, but similarly, some girls with the full mutation may have no symptoms and therefore lead a life “normally” and only when they have children might they discover the condition.
Many children and adults show autistic-like features, including avoiding eye contact, anxiety in social situations, insistence on familiar routines and hand flapping or hand biting. Although many people with fragile X relate well to others, anxiety in unfamiliar or unpredictable situations may cause them to act in this way. A substantial number of individuals with fragile X will show greater problems relating to others and may receive a dual-diagnosis of autism. Speech and language are usually delayed with continuing speech and communication problems. Some children and adults develop epilepsy.
Some strengths associated with Fragile X
People with Fragile X are often described as very likeable, showing a sensitive side. Imitation skills can be good, with an affinity to visual learning with good long term memory. Families will often talk about their houses being filled with loving and Fragile X people having a great sense of humour!
Can you see Fragile X in someone?
There are some physical features associated with Fragile X, including a long narrow face with prominent jawbones and ears. However, these are rarely obvious in young children. The lack of distinguishing features is one of the reasons that diagnosis can be delayed. You cannot tell that someone has Fragile X just based upon their appearance or behaviour. The only way to tell if someone has Fragile X Syndrome is to do a genetic test.
What causes Fragile X?
The root cause of Fragile X is unknown, but Fragile X syndrome is caused by a mutation in which a DNA segment, known as the CGG triplet repeat, is expanded within the FMR1 gene. “Neuro Typical” people are considered to have up to 45 repeats of the CGG sequent. While pre-mutation carriers have up to 199 repeats and Fragile X people are seen as 200 and more repeats.
It is unclear as to why we under-go an expansion of the CGG repeats through generations, this expansion leads “Neuro Typical” people to become Pre-Mutations carriers and similarly Pre-Mutations carriers to bare “full mutation” children. This is a very clinical and scientific description that we do not like at Gene Works! No one is “mutated” the condition while affecting many areas is largely invisible to the eye and the characteristics of a Fragile X person that shines over all else is their loving nature, a want to help others, and their brilliant sense of humour!
Tell me more about FMRP
FMRP is an RNA binding protein expressed in the brain coded by the FMRI gene located at Xq27.3 that has been linked to Fragile X syndrome (FXS) and with growing evidence for an association with Autism Spectrum Disorder (ASD).
Our Research
CGG Repeats – A deep look
We wish to understand the relationship in CGG repeats in “Neurotypical”, Pre Mutation and Fragile X people. We will search for commonality in the sequence. Do we all have the same start, middle and end for example.
FMRP – But how quiet is it?
People with Fragile X Syndrome (FXS) are thought to have a silence of the FMR Protein. However Fragile X is a spectrum, as we see in autism, so is it not more logical that FRMP levels reduce with extended repeats rather than simple “on” before 200 CGG repeats and “off” after 200?
We will determine the level of FRMP present at different CGG repeats and if either specific CGG sequences stimulate FMRP or if the reduction of CGG repeats alters levels of FMRP.
To Activate or Deactivate – That is the question!
Two thirds of females with full Fragile X extension (FXS) show no symptoms where 100% of boys do. This is because females have two X chromosomes, one from Mum and one from Dad. Researchers from the University of California Los Angeles (UCLA) have observed higher levels of father to daughter X inactivation in autoimmune diseases. Our interest is in this relationship between mums X and dads X chromosomes and if we can find methylation regulators which will activate or deactivate one over the other. We will target these differences, if present, and therefore we may be able to activate the inactive X in stages and therefore unlock new treatment strategies.
FMRP, ASD and the Gene Works Project
Using our expertise and knowledge of the relationship with FMRP, we will look at the development of neural pathway and accumulate evidence for an association with Autism Spectrum Disorder (ASD) it has not yet been confirmed using common variants from genome-wide association studies but using our Gene Works Project, we hypothesis this will change as we look at the broadest ever spectrum of people with both methylated and unmethylated levels of FMRP.
One small edit for man…
Using cutting edge techniques such as Prime Editing using CRISPR and CAS variants we are exploring the possibilities of editing the FMR1 Gene to reduce the number of CGG repeats with a positive and manageable change effect. As Fragile X is a mutation and extension in the CGG repeats, understanding the CGG relationship in our “deep look” research will help us to understand if removing a repeat is necessary or if trimming the extension to introduce low levels of FMRP is possible. Our Gene Works Project is absolutely crucial and will allow us to compare Neurotypical and FXS FMR1 genes and the CGG repeat.
Nano Containers – Can they deliver a life-changing payload?
Investigating the use of nanosize containers that can slip inside cells and deliver protein-based medicines and gene therapies which are attached to CRISPR is an exciting and novel approach being developed by scientists at John Hopkins Medicine. We would like to investigate the potential of delivering FRMP via nano containers.
Fragile X seems well-suited for CRISPR gene therapy because it targets a specific type of cell. Other inherited diseases such as cystic fibrosis and muscular dystrophy may be more difficult to treat because they affect different cell types in different organs. Our research is not about discovering the editing techniques but about putting them into a practical and safe application using our extensive knowledge gained from the research you help to fund.
We are still a very early stage startup organisation.
Please feel free to get in touch and ask us anything.