Recent studies of complex brain disorders such as schizophrenia and autism spectrum disorder (ASD) have identified a few "master keys," risk genes that sit at the center of a network of genes important for brain function. Researchers at Emory and the Chinese Academy of Sciences have created mice partially lacking one of those master keys, called MIR-137, and have used them to identify an angle on potential treatments for ASD.
The results were published this Read more
A genetic disorder caused by silencing of a gene on the X chromosome, fragile X syndrome affects about one child in 5,000, and is more common and more severe in boys. It often causes mild to moderate intellectual disabilities as well as behavioral and learning challenges.
Amy Talboy, MD
The gene responsible for fragile X syndrome, the most common inherited form of intellectual disability, was identified more than 25 years ago. Emory genetics chair Stephen Warren played a major role in achieving that milestone. His work led to insights into the molecular details of learning and memory, and nationwide clinical trials — which have a more complicated story.
Treating the molecular basis of a neurodevelopmental disorder, instead of simply addressing symptoms, is a lofty goal – one that remains unfulfilled. Now a new study, supported by the National Institute of Neurological Disorders and Stroke, is reviving a pharmacological strategy that Warren had a hand in developing.
“This is a very well thought out approach to studying changes in language and learning in children who are difficult to test,” says Amy Talboy, medical director of Emory’s Down Syndrome and Fragile X clinics, who is an investigator in the NINDS study. “It could change how we conduct these types of studies in the future.” Read more
Research in mice shows that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.
The results were published online last week by Neuropsychopharmacology, and were presented at the NFXF International Fragile X Conference in Cincinnati.
When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with fragile X syndrome.
The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in fragile X syndrome; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.
“Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine.
“Right now, no proven efficient treatments are available for fragile X syndrome that are targeted to the disease mechanism,” says Christina Gross, PhD, from Cincinnati Children’s. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.”
The paper represents a collaboration between three laboratories: two at Emory led by Bassell and Shannon Gourley, PhD, and one at Cincinnati Children’s, led by Gross. Gourley is based at Yerkes National Primate Research Center; see this earlier item on her collaboration with Bassell here.
While the researchers are discussing clinical trials of p110β inhibitors in fragile X syndrome, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. More here.
With respect to clinical trials, the fragile X community has been disappointed before. Based on encouraging studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures, the ages of study participants and drug tolerance may have played a role.
Congratulations to Christine Dunham and colleagues in the Department of Biochemistry for their first cryo-electron microscopy paper, recently published in the journal Structure.
The paper solves the structure of a bacterial ribosome bound to a messenger RNA containing a loop that regulates translation. This process is important for the study of several neurological diseases such as fragile X syndrome, for example.
Christine Dunham, PhD
Dunham writes: “We are focusing on establishing this in bacteria to understand frameshifting and protein folding as a consequence of codon preference. We will then build up our knowledge to potentially study eukaryotic translational control.”
Construction now underway in the Biochemistry Connector will allow installation of microscopes (worth $6 million) necessary for Dunham and others to do cryo-EM here at Emory, although she advises that it will be several months until they are photo-op ready. For the Structure paper, Dunham collaborated with George Skiniotis at University of Michigan; he recently moved to Stanford. Read more
We can learn a lot about somebody from the friends they hang out with. This applies to people and also to genes and proteins. Emory scientists have been investigating a gene that we will call — spoiler alert — “Friend of fragile X.”
Fragile X syndrome is the most common inherited form of intellectual disability, studied by research teams around the world with drug discovery and clinical trials in mind. It is caused by a disruption of the gene FMR1.
The findings provide new insight into the function of FMR1 as well as ZC3H14; the evidence comes from experiments performed in fruit flies and mice. The most recent paper is in the journal Cell Reports (open access), published this week.
The scientists found that the proteins encoded by FMR1 and ZC3H14 stick together in cells and they hang out in the same places. The two proteins have related functions: they both regulate messenger RNA in neurons, which explains their importance for learning and memory.
The fragile X protein (FMRP) was known to control protein production in response to signals arriving in neurons, but the Cell Reports paper shows that FMRP is also regulating the length of “tails” attached to messenger RNAs – something scientists did not realize, even after years of studying FMRP and fragile X, Moberg says.
To be sure, FMRP interacts with many proteins and appears to be a critical gatekeeper. Emory geneticist Peng Jin, who has conducted his share of research on this topic, says that “FMRP must be very social and has a lot of friends.” More here.
A PNAS paper published MondayÂ demonstrates the kinds of insights that can be gleaned from a large scale sequencing project examining the fragile X gene.
Most children (boys, usually) who have fragile X syndrome have a particular mutation. An expanded â€œtriplet repeatâ€ stretch of DNA, which is outside the protein-coding region of the gene, puts the entire gene to sleep.
At Emory,Â geneticist Steve Warren, cell biologist Gary Bassell and colleagues have been identifying less common changesÂ in the fragile X gene by looking in boys who are developmentally delayed, but donâ€™t have the triplet repeat expansion. The first author of the paper is former postdoc Joshua Suhl, now at Booz Allen Hamilton in Massachusetts.
The authors describe two half-brothers who have the same genetic variant, which changes how production of the FMRP protein is regulated.Â These examples show that the fragile X gene is so central to how neurons function that several kinds of geneticÂ glitches in it can make this finely tuned machine break down.
â€œThis is a hot area and not much is known about it,â€ Warren says. Read more
New research in mice strengthens a potential strategy for treating fragile X syndrome, the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorder.
The results, published April 23 inÂ Cell Reports, suggest that a drug strategy targeting a form of the enzyme PI3 (phosphoinositide-3) kinase could improve learning and behavioral flexibility in people with fragile X syndrome. The PI3 kinase strategy represents an alternative to one based on drugs targeting mGluR5 glutamate receptors, which have had difficulty showing benefits in clinical trials.
Research led by Emory scientistsÂ Gary Bassell, PhD and Christina Gross, PhD had previously found that the p110Î² form of PI3 kinase is overactivated in the brain in a mouse fragile X model, and in blood cells from human patients with fragile X syndrome.
Now they have shown that dialing back PI3 kinase overactivation by using genetic tools can alleviate some of the cognitive deficits and behavioral alterations observed in the mouse model. Drugs that target the p110Î² form of PI3 kinase are already in clinical trials for cancer.
“Further progress in this direction could lead to a clinical trial in fragile X,” says Bassell, who is chair of Cell Biology at Emory University School of Medicine. “The next step is to test whether this type of drug can be effective in the mouse model and in human patient cells.” Read more
A new paper in PNAS from geneticist Steve Warren and colleagues illustratesÂ the complexity of the protein disrupted in fragile X syndrome. It touches on how proposed drug therapies that address one aspect of fragile X syndrome may not be able to compensate for all of them. [For a human side of this story, read/listen to this recent NPR piece from Jon Hamilton.]
Fragile X syndrome is the most common single-gene disorder responsible for intellectual disability. Most patients with fragile X syndrome inherit it because a repetitive stretch of DNA, which is outside the protein-coding portion of the fragile X gene, is larger than usual. The expanded number of CGG repeats silences the entire gene.
However, simple point mutations affecting the fragile X protein are possible in humans as well. In the PNAS paper, Warren’s team describes what happens with a particularly revealing mutation, which allowed researchers to dissect fragile X protein’s multifaceted functions. Read more
A studyÂ published in Pediatrics this week tracks “adaptive behavior” asÂ children and adolescents with fragile X syndrome are growing up. This isÂ the largest longitudinal study to date in fragile X, which isÂ the leading inherited cause of intellectual disability and the leading single-gene risk factor for autism spectrum disorder.
Adaptive behavior covers a range of everyday social and practical skills, including communication, socialization, and completing tasks of daily living such as getting dressed. In this study, socialization emerged as a relative strength in boys with fragile X, in that it did not decline as much as the other two domains of adaptive behavior measured: communication and daily living skills.
The “socialization as relative strength in fragile X” findings meshes with a growing awareness in the autism field, summarized nicely here by Jessica Wright at the Simons Foundation Autism Research Initiative, thatÂ fragile X syndrome symptoms are often distinct from those in autism spectrum disorder.
One key distinction between the disorders, for example, is in social interactions. Children with autism and those with fragile X syndrome both shy away from social contact, have trouble making friends and avert their gaze when people look at them.
But children with fragile X syndrome often sneak a peek when the other person turns his back, researchers say. Children with autism, in contrast, seem mostly uninterested in social interactions.
â€œChildren with fragile X syndrome all have very severe social anxiety that plays a big role in the perception that they have autism,â€ saysÂ Stephen Warren, professor of human genetics at Emory University School of Medicine in Atlanta. â€œThey are actually interested in their environment; they are just very shy and anxious about it.â€
A clinical trial testing a therapy for children with fragile X syndrome is closing down, after the sponsoring company announced that the drug, called arbaclofen, was not meeting its goals.
Readers of Emory Health magazine may remember Samuel McKinnon, an arbaclofen study participant who was featured in a 2012 article and video (below).
â€œWe were surprised,â€ Samuelâ€™s mother Wendy told us Monday. â€œBut we knew going in that there were no guarantees.â€
She reports that Samuel has made significant progress in the last couple of years. He likes playing and talking with the family’s new puppy, Biscuit. Samuel’s language skills have Ray Ban outlet blossomed and he will be headed to second grade this fall. But itâ€™s hard to say whether thatâ€™s mainly because of the experimental drug or because Samuel has been continuing to grow and work hard in school and in therapy, she says.
A sizable fraction of patients in the study appeared to benefit from the drug, just not the majority of them, says Emory genetics chair Steve Warren.