Fragile X Syndrome Research Gains Momentum

With the help of a new human embryonic stem cell line, researchers make initial strides toward treatment for the genetic mutation.

7:00 AM

Author | Kelly Malcom

Fragile X syndrome is the most common inherited cause of intellectual disability and autism and poses a significant burden to affected families. The syndrome gets its name because — under a microscope — part of the X chromosome in affected individuals appears broken or fragile.

Because males have only one X chromosome, as opposed to two in females, they are typically more severely affected by the Fragile X mutation. While there is no cure, researchers have been studying the gene responsible for Fragile X, called FMR1, to find a viable treatment.

LISTEN UP: Add the new Michigan Medicine News Break to your Alexa-enabled device, or subscribe to our daily audio updates on iTunes, Google Play and Stitcher.

Genes contain the instructions to make proteins. A genetic mutation is like an instruction manual full of gibberish instead of recognizable words.

A dangerous repeat

In the case of Fragile X, a "word" made up of three nucleotides, CGG, is repeated hundreds of times in the FMR1 gene instead of the normal 25 to 40 repeats. This high repetition deactivates the gene through a process called methylation, and it leads to a loss of the protein FMRP. That lack of FMRP leads to seizures, anxiety, learning difficulties and other Fragile X symptoms.

Michigan Medicine researchers have been working with human embryonic stem cells (hESCs) donated by a couple with the Fragile X mutation to try to reactivate production of the protein.

The stem cell line itself, developed by Gary Smith, Ph.D., a professor of molecular and integrative physiology and of obstetrics and gynecology and the director of Michigan's MStem Cell Laboratories, is a critical development for the field of Fragile X research.

SEE ALSO: A Drug Makes Stem Cells 'Embryonic' Again

"There are many reasons why we do these experiments in human embryonic stem cells," says senior researcher Peter Todd, M.D., Ph.D., associate professor of neurology. "First, humans and mice are not the same, especially when you're talking about autism and intellectual disability. Additionally, the way the gene turns off doesn't happen in mice, so we can't institute the state the disease occurs in in order to correct it."

With the new hESC line, the researchers saw that as the cells grew, the gene was initially turned on and transcribing at near normal levels. However, they stopped making RNA over time. Todd suspects that making RNA with a large repeat is somehow unhealthy for the cells and that the cells that turned off the gene survived.

The question remained: What happens if the troublesome repeat was turned back on? The team used a powerful cellular tool to target the repeat and observe what would happen to the protein-making process.

Humans and mice are not the same, especially when you're talking about autism and intellectual disability.
Peter Todd, M.D., Ph.D.

An attempt at reactivation

CRISPR-Cas9 has become popular recently for its ability to edit DNA. However, the team used a slightly different form, CRISPR-dCas9, to deliver a special activator protein specifically to the site of the abnormally large repeat on the FMR1 gene. Once there, the attached protein was used to reactivate the gene and get it to transcribe once more.

MORE FROM MICHIGAN: Sign up for our weekly newsletter

"The fact that we can see that effect even at large repeat lengths that are fully silenced suggests that dCas9 can recognize the sequence," Todd says.

Theoretically, this should be enough to generate FMRP. And in normal cells, researchers saw an increase in the protein. However, "at 800 to 900 repeats, we were getting activation at the transcription level but not very much protein," Todd says. Possible explanations for this discrepancy range from incomplete delivery of the activator to cells to the size of the repeat itself. Despite this, the study provides new hope for researchers by demonstrating that FMR1 can be targeted and reactivated.

SEE ALSO: Turn a Cell into Any Other Kind of Cell, No Magic Wand Required

Since the goal is to make enough FMRP, the group plans to compare this approach to others with different cell lines, repeat sizes and degrees of methylation. The researchers say even small successes with reducing methylation, increasing transcription and increasing the production of FMRP could result in reduced symptoms for patients.

Their paper is published in Frontiers in Molecular Neuroscience.

More Articles About: Lab Report Genetic Disorders Stem Cells Growth and Development Basic Science and Laboratory Research Developmental Milestones Genetics
Health Lab word mark overlaying blue cells
Health Lab

Explore a variety of healthcare news & stories by visiting the Health Lab home page for more articles.

Media Contact Public Relations

Department of Communication at Michigan Medicine

[email protected]


Stay Informed

Want top health & research news weekly? Sign up for Health Lab’s newsletters today!

Featured News & Stories purple all notifications on phone teen sleeping in bed with phone next to them
Health Lab
Study: Average teen received more than 200 app notifications a day
A Michigan Medicine expert explains more of a report’s key findings on cell phone use and how parents can support a healthy use of technology.
cells colorful
Health Lab
Improvements in human genome databases offer a promising future for cancer research
A gene sequencing method called ribosome profiling has expanded our understanding of the human genome by identifying previously unknown protein coding regions. Also known as Ribo-seq, this method allows researchers to get a high-resolution snapshot of protein production in cells.
flies moving sled in snow with person
Health Lab
Gene links exercise endurance, cold tolerance and cellular maintenance in flies
A study in PNAS identifies a protein that, when missing, makes exercising in the cold that much harder—that is, at least in fruit flies.
bacteria black background yellow cell
Health Lab
The surprising origin of a deadly hospital infection
Surprising findings from a Michigan Medicine study in Nature Medicine suggest that the burden of C. diff infection may be less a matter of hospital transmission and more a result of characteristics associated with the patients themselves.
Health Lab
Genetic mutation linked to adrenal tumor and hypertension
Research from the Department of Molecular & Integrative Physiology at Michigan Medicine identifies a previously unknown genetic mutation that causes the disease called primary aldosteronism in certain populations.
dogs collage
Health Lab
Dog diversity unveiled by international DNA database
A new paper, published in the journal Genome Biology, outlines what the Dog10K project discovered after sequencing the genomes of close to 2,000 samples from 321 different breed dogs, wild dogs, coyotes, and wolves, and comparing them to one reference sample—that of a German Shepherd named Mischka.