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The Fragile X syndrome affects more than the brain

A new study born of the collaboration of a team from the Institute of Molecular and Cellular Pharmacology (IPMC), the Valrose Institute of Biology (iBV) (1) and various European contributors describes in detail, for the first time, the peripheral effects of the mutation responsible for the Fragile X syndrome.

Publication : 15/03/2019
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Less known by general public than Down syndrome, the Fragile X syndrome remains the first hereditary cause of intellectual disability and the first identified genetic cause of autism, affecting one person out of approximately 6,000. The syndrome is due to a mutation on the X chromosome, resulting in the absence of FMRP (Fragile X Mental Retardation Protein) in the body. This protein usually binds with the messenger RNA, i.e. the genetic material derived from DNA, which contains the information needed to manufacture proteins. Many RNA-binding proteins such as FMRP regulate protein expression by activating or inhibiting the translation of messenger RNA. 

Given the predominant symptoms induced by the absence of FMRP, researchers had attempted so far to understand the consequences of its absence in the brain and neurons. But a new study, carried out jointly by an IPMC team, the iBV (1) and European collaborators (from Belgium, Germany, and the United Kingdom), describes in detail for the first time the peripheral effects of the mutation on the gene responsible for the disease, using the mouse model for Fragile X syndrome and by analyzing patient blood samples. 

The researchers examined the metabolome, i.e. all the very small molecules produced in the body and circulating in the blood, including glucose or lipids, for example. They then observed, in the Fragile X mouse, a profile that seemed to be the opposite of what is observed in diabetes or obesity. The glucose level was lower than average, as were insulin, cholesterol and triglyceride levels. These last disturbances in particular, could have been due to an abnormal increase, in the liver, of the production of proteins involved in lipid degradation. In the absence of FMRP, the mouse's metabolism fed on lipids instead, which also contributed to reducing its body fat. It remains to be discovered why the mouse had a glucose deficiency. "It could be an indirect consequence of the phenomenon identified in the liver, or the result of a mechanism of compensation between organs,"explains Laetitia Davidovic, researcher at the IPMC and corresponding author of the article on this subject published in the Molecular Metabolismjournal. 

In terms of clinical applications, "we were able to demonstrate that metabolic markers were also affected in the serum of patients with Fragile X, which indicates that some of our results could be transposed to humans," says the researcher. For her, these data should be taken into account in the therapeutic strategies developed to improve the behavioral symptoms of patients with X-Fragile. Some drugs may have significant side effects, not only in the brain but elsewhere, and particularly on the metabolism. 

1. Antoine Leboucher, Patricia Bermudez-Martin and Laetitia Davidovic for the IPMC. Didier Pisani and Ez-Zoubir Amri for the iBV 

Figure: loss of adipose tissue in Fragile X mice 

 Figure montrant la perte de tissu adipeux des souris X fragile