By Michael Smith, North American Correspondent, MedPage Today
Published: December 19, 2007
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

CAMBRIDGE, Mass., Dec. 19 — Altering just one gene allowed researchers here to correct many aspects of fragile X syndrome in mice.

• Fragile X syndrome is the most common heritable form of mental retardation and also the leading identified cause of autism.
• Add that loss of a single gene has been shown to be the basis of the syndrome, but the exact pathogenesis remains unclear.
• Note that this study, conducted in experimental mice, suggests that loss of the fragile X gene allows the product of a second gene to run amok, causing many of the symptoms of the syndrome.

The finding offers the possibility of therapy for the syndrome, which is the most common heritable form of mental retardation and the leading identified cause of autism, according to Mark Bear, Ph.D., of the Massachusetts Institute of Technology, and colleagues.

The loss of the gene for fragile X mental retardation protein (FMRP) is known to cause the syndrome, but it hasn’t been clear exactly how, Dr. Bear and colleagues said in the Dec. 20 issue of Neuron.

A series of experiments in mice that lack the equivalent of the fragile X gene appear to show that FMRP acts as a brake on a second protein, a metabotropic glutamate receptor dubbed mGluR5, the researchers said.

Reapplying the brake by reducing the expression of mGluR5 prevented aspects of the syndrome, the researchers said, including a tendency to seizures, altered body growth, and a different pattern of brain structure and function.

The “constellation of findings,” the researchers concluded, implies that “fragile X is a disorder of excess … and these excesses can be corrected by reducing mGluR5.”

Dr. Bear and colleagues experimented with four lineages of mice — wild-type mice, mice lacking FMRP but not mGluR5, mice with FMRP but lacking one of the two mGluR5 alleles, and mice without FMRP and lacking one of the two mGluR5 alleles.

Missing one of the mGluR5 alleles reduced expression of the protein by 50%, the researchers said.

The animals lacking FMRP but with fully functioning mGluR5 (dubbed KO mice) exhibited many of the aspects of fragile X seen in humans with the condition, while those without FMRP but with a lowered expression of mGluR5 (dubbed CR mice) were similar to wild-type.

For example, an increased density of dendritic spines on neurons, the major targets of excitatory synapses in the brain, is associated with fragile X in humans.

Similar abnormal neurons were seen in the KO mice, the researchers said, but not in the CR animals.

The KO mice — whose wild-type ancestors are resistant to seizures — have a tendency to epilepsy-like convulsions in response to certain tones, which is a consequence of the loss of FMRP, the researchers said.

In this study, 72% of the KO animals seized when exposed to the tone, compared with none of the wild-type mice, a difference that was significant at P<0.0001. But the tendency to seizure was significantly attenuated (P=0.028) in the CR mice, the researchers said.

Humans with fragile X show accelerated prepubescent growth and the KO mice also showed a 10% increase in average weight within a few days of weaning, compared with wild-type and CR animals. The differences were significant at P=0.017 and P=0.004, respectively.

The data show “unambiguously” that the two proteins oppose each other, the researchers concluded, and support the idea that many aspects of fragile X are the result of unopposed activation of mGluR5.

Macro-orchidism is also a feature of the fragile X syndrome, however, there was no evidence of an interaction between FMRP and mGluR5 in the control of testicle size in the mice.

Primary source: Neuron
Source reference: Dölen G, et al “Correction of fragile X syndrome in mice” Neuron 2007; 56: 955-62.

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FRAXA Research Foundation is a parent run organization that funds research to find effective treatments and, ultimately, a cure for Fragile X. Fragile X is the leading inherited cause of mental retardation and the most common genetic cause of autism.

Fragile X is caused when a gene fails to produce a single protein necessary for normal brain function. There is a 50% chance of inheriting the Fragile X gene when one parent is a carrier. As parents of children with Fragile X, we understand first-hand the stress Chris Benoit and his wife might have been coping with. At birth many children with Fragile X seem normal and are often not diagnosed until two or three years of age when the child fails to meet typical developmental milestones. The initial shock of learning that your child is mentally impaired, followed by the continued emotional and financial strain of finding appropriate schools, child care and therapies can be an overwhelming emotional and financial burden for many families. Some of the symptoms Fragile X can cause are — severe anxiety, impaired learning, debilitating sensory integration problems, very limited (or possibly no) speech, obsessive compulsive behaviors, and even seizures — making day-to-day life extremely challenging. Most children with Fragile X have a normal life expectancy creating an added burden on parents to plan for their child’s future.

FRAXA funds biomedical research, in the US and internationally, aimed at treating and curing Fragile X. Currently FRAXA has numerous treatments for Fragile X in development in collaboration with pharmaceutical companies worldwide. FRAXA’s basic research, like the recently announced therapeutic potential of PAK inhibition, points the way toward innovative drug therapies for Fragile X and related disorders like autism.

According to the Centers for Disease Control, FXS affects 1 in 4,000 males and 1 in 6,000 females of all races and ethnic groups. The prevalence of autism ranges from 1 in 500 to 1 in 166 children. Currently there is no effective treatment for FXS and other types of autism.

FRAXA Research Foundation

http://www.fraxa.org

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NEW HAVEN, Conn., June 8 (UPI) — U.S. researchers have identified a new regulatory target for the Fragile X mental retardation protein, laying the groundwork for possible new treatments.

Fragile X syndrome, or FXS, is the leading inherited form of mental retardation.

The findings, published in the early online edition of the Proceedings of the National Academy of Sciences, also have implications for autism, which shares a common physiological pathway with FXS, according to researchers at the Yale School of Medicine.

The research team, led by Dr. Yingqun Huang, previously found that FMRP — a protein without which brain development is hampered and nerve cells cannot communicate with each other — interacts with nuclear mRNA export protein NXF2 in the mouse brain and testes.

“Our findings explain why the NXF1 protein level is much lower in the hippocampal — brain — neurons involved in learning and memory than in many other cells,” Huang said in a statement.

“This may suggest that a high level of NXF1 might hinder the function of these cells.”

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