The Fragile X Syndrome


Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the first genetic cause of autism spectrum disorders, affecting approximately 1/7000 females and 1/4000 males worldwide. The syndrome is due to the silencing of a single X‐linked gene, the FRAGILE X MENTAL RETARDATION 1 (FMR1) gene. Patients affected by FXS display a variety of physical and mental phenotypic traits. In the last 25 years, research advances in the fragile X syndrome field have led to a better understanding of its molecular bases as well as of the pleiotropic phenotypic effects due to the absence of the FMR1 gene product, the mRNA (messenger ribonucleic acid) translation regulator coined as fragile X mental retardation protein (FMRP).

Key Concepts

  • Fragile X Syndrome (FXS) is an inherited neurodevelopmental disorder and a trinucleotide repeat disorder.
  • FXS is a frequent cause of intellectual disability and autism.
  • FXS is caused by the silencing of a single X‐linked gene, the FMR1 gene.
  • The full mutation is reached when CGG repeats in the FMR1 gene exceed 200, causing loss‐of‐function of the gene.
  • FMR1 premutation with intermediate CGG repeats is linked to premature ovarian failure and tremor‐ataxia syndrome.
  • FMR1 gene encodes a widely expressed protein regulating mRNA translation.
  • FMR1 gene controls brain development and neurogenesis.
  • FXS is associated with brain and synaptic morphology anomalies.

Keywords: intellectual disability; autism; Fragile X Syndrome; neurodevelopmental disorder; trinucleotide repeat disease; RNA‐binding protein; translation; synaptic plasticity; dendritic spine; RNA granule

Figure 1. Portraits of children affected with fragile X syndrome. Courtesy of Dr. Carlo Paribello MD, President of the Fragile X Research Foundation of Canada.
Figure 2. Molecular bases of the fragile X Syndrome. A normal, a premutated and a mutated X‐chromosome are represented, and the consequences induced by the different expansions of the CGG repeats are illustrated.
Figure 3. Morphology of neurons carrying spines from an Fmr1‐knockout mouse (a) as compared to normal neurons from a wild‐type mouse (b). Note the long, thin and tortuous dendritic spines and the increased spine density in the knock‐out neuron, characteristics of developing immature spines. Reproduced from Comery et al. 1997 © National Academy of Sciences, USA.
Figure 4. Model proposing the involvement of FMRP (fragile X mental retardation protein) in trafficking of neuronal granules containing mRNA (messenger ribonucleic acid) that are exported from the cell body (soma) to distal locations such as dendritic spines, synapses (one dendritic spine forms half a synapse) or axons. High levels of FMRP are present in granules to repress mRNAs. Inset: granules sliding on microtubules as seen by electron microscopy. Bar represents 500 nm. Adapted from Bardoni et al. 2006 © Cambridge University Press.


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Further Reading

Bassell GJ and Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60 (2): 201–214.

Chelly J and Mandel JL (2001) Monogenic causes of X‐linked mental retardation. Nature Reviews. Genetics 2 (9): 669–680.

Gross C, Hoffmann A, et al. (2015) Therapeutic strategies in fragile X syndrome: from bench to bedside and back. Neurotherapeutics 12 (3): 584–608.

Hagerman RJ and Hagerman PJ (2002) Fragile X Syndrome: Diagnosis, Treatment and Research. Baltimore, MD: The Johns Hoptins University Press.

Kidd SA, Lachiewicz A, et al. (2014b) Fragile X syndrome: a review of associated medical problems. Pediatrics 134 (5): 995–1005.

Li Y and Zhao X (2014) Fragile X proteins in stem cell maintenance and differentiation. Stem Cells 32 (7): 1724–1733.

O'Donnell WT and Warren ST (2002) A decade of molecular studies of fragile X syndrome. Annual Review of Neuroscience 25: 315–338.

Sung Y‐J and Denman RB (2005) The Molecular Basis of Fragile X Syndrome Research Signpost. Kerala: Research Signpost.

Tranfaglia M (2004) Medication Guide for Fragile X. Newburyport: FRAXA Research Foundation.

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Khandjian, Edouard W, Robert, Claude, Khalfallah, Olfa, and Davidovic, Laetitia(Oct 2017) The Fragile X Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005533.pub2]