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. © 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. © Cambridge University Press.


Abitbol M, Menini C, et al. (1993) Nucleus basalis magnocellularis and hippocampus are the major sites of FMR‐1 expression in the human fetal brain. Nature Genetics 4 (2): 147–153.

Alisch RS, Wang T, et al. (2013) Genome‐wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus. BMC Medical Genetics 14: 18.

Bardoni B, Davidovic L, Bensaid M and Khandjian EW (2006) The fragile X syndrome: exploring its molecular basis and seeking a treatment. Expert Reviews in Molecular Medicine 8 (8): 1–16.

Berman RF and Willemsen R (2009) Mouse models of fragile X‐associated tremor ataxia. Journal of Investigative Medicine 57 (8): 837–841.

Buijsen RA, Visser JA, et al. (2016) Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat‐associated non‐AUG translation plays a role in fragile X‐associated primary ovarian insufficiency. Human Reproduction 31 (1): 158–168.

Collins SC, Bray SM, et al. (2010) Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males. American Journal of Medical Genetics. Part A 152A (10): 2512–2520.

Comery TA, Harris JB, Willems PJ, et al. (1997) Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proceedings of the National Academy of Sciences of the United States of America 94: 5401–5414.

Consortium TD‐BFX (1994) Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 78 (1): 23–33.

Darnell JC and Klann E (2013) The translation of translational control by FMRP: therapeutic targets for FXS. Nature Neuroscience 16 (11): 1530–1536.

Darnell JC, Van Driesche SJ, et al. (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146 (2): 247–261.

Devys D, Lutz Y, et al. (1993) The FMR‐1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nature Genetics 4 (4): 335–340.

Dury AY, El Fatimy R, et al. (2013) Nuclear fragile X Mental retardation protein is localized to Cajal bodies. PLoS Genetics 9 (10): e1003890.

El Fatimy R, Davidovic L, et al. (2016) Tracking the fragile X mental retardation protein in a highly ordered neuronal ribonucleoparticles population: a link between stalled polyribosomes and RNA granules. PLoS Genetics 12 (7): e1006192.

Graber TE, Hebert‐Seropian S, et al. (2013) Reactivation of stalled polyribosomes in synaptic plasticity. Proceedings of the National Academy of Sciences of the United States of America 110 (40): 16205–16210.

Greco CM, Berman RF, et al. (2006) Neuropathology of fragile X‐associated tremor/ataxia syndrome (FXTAS). Brain 129 (1): 243–255.

Groh M, Silva LM, et al. (2014) Mechanisms of transcriptional dysregulation in repeat expansion disorders. Biochemical Society Transactions 42 (4): 1123–1128.

Guduric‐Fuchs J, Mohrlen F, et al. (2004) A fragile X mental retardation‐like gene in a cnidarian. Gene 343 (2): 231–238.

Hagerman RJ, Berry‐Kravis E, et al. (2009) Advances in the treatment of fragile X syndrome. Pediatrics 123 (1): 378–390.

Hagerman RJ and Hagerman P (2016) Fragile X‐associated tremor/ataxia syndrome ‐ features, mechanisms and management. Nature Reviews. Neurology 12 (7): 403–412.

He CX and Portera‐Cailliau C (2013) The trouble with spines in fragile X syndrome: density, maturity and plasticity. Neuroscience 251: 120–128.

Hoeft F, Carter JC, et al. (2010) Region‐specific alterations in brain development in one‐ to three‐year‐old boys with fragile X syndrome. Proceedings of the National Academy of Sciences of the United States of America 107 (20): 9335–9339.

Huot ME, Bisson N, et al. (2005) The RNA‐binding protein fragile X‐related 1 regulates somite formation in Xenopus laevis. Molecular Biology of the Cell 16 (9): 4350–4361.

Irwin SA, Patel B, et al. (2001) Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile‐X syndrome: a quantitative examination. American Journal of Medical Genetics 98 (2): 161–167.

Jacquemont S, Hagerman RJ, et al. (2004) Penetrance of the fragile X‐associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291 (4): 460–469.

Jin P, Duan R, et al. (2007) Pur alpha binds to rCGG repeats and modulates repeat‐mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron 55 (4): 556–564.

Khalfallah O, Jarjat M, et al. (2017) Depletion of the fragile X mental retardation protein in embryonic stem cells alters the kinetics of neurogenesis. Stem Cells 35 (2): 374–385.

Khandjian EW, Corbin F, et al. (1996) The fragile X mental retardation protein is associated with ribosomes. Nature Genetics 12 (1): 91–93.

Khandjian EW, Fortin A, et al. (1995) A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture. Human Molecular Genetics 4 (5): 783–789.

Khandjian EW, Huot ME, et al. (2004) Biochemical evidence for the association of fragile X mental retardation protein with brain polyribosomal ribonucleoparticles. Proceedings of the National Academy of Sciences of the United States of America 101 (36): 13357–13362.

Khandjian EW, Tournier B, et al. (2009) RNA granules: functions within presynaptic terminals and postsynaptic spines. In: Squire LW (ed) Encyclopedia of Neuroscience, pp. 389–395. London: Oxford Press.

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

Lubs HA (1969) A marker X chromosome. American Journal of Human Genetics 21 (3): 231–244.

McConkie‐Rosell A, Lachiewicz AM, et al. (1993) Evidence that methylation of the FMR‐I locus is responsible for variable phenotypic expression of the fragile X syndrome. American Journal of Human Genetics 53 (4): 800–809.

Mientjes EJ, Nieuwenhuizen I, et al. (2006) The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo. Neurobiology of Disease 21 (3): 549–555.

Mulligan LM, Phillips MA, et al. (1985) Genetic mapping of DNA segments relative to the locus for the fragile‐X syndrome at Xq27.3. American Journal of Human Genetics 37 (3): 463–472.

Nolin SL, Brown WT, et al. (2003) Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. American Journal of Human Genetics 72 (2): 454–464.

Oberle I, Rousseau F, et al. (1991) Instability of a 550‐base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252 (5010): 1097–1102.

Penagarikano O, Mulle JG, et al. (2007) The pathophysiology of fragile x syndrome. Annual Review of Genomics and Human Genetics 8: 109–129.

Quartier A, Poquet H, et al. (2017) Intragenic FMR1 disease‐causing variants: a significant mutational mechanism leading to Fragile‐X syndrome. European Journal of Human Genetics 25 (4): 423–431.

Richter JD, Bassell GJ, et al. (2015) Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nature Reviews. Neuroscience 16 (10): 595–605.

Rousseau F, Heitz D, et al. (1991) Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. New England Journal of Medicine 325 (24): 1673–1681.

Sherman SL (2000) Premature ovarian failure in the fragile X syndrome. American Journal of Medical Genetics 97 (3): 189–194.

Stefani G, Fraser CE, et al. (2004) Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. Journal of Neuroscience 24 (33): 7272–7276.

Tassone F, Iwahashi C, et al. (2004) FMR1 RNA within the intranuclear inclusions of fragile X‐associated tremor/ataxia syndrome (FXTAS). RNA Biology 1 (2): 103–105.

Todd PK, Oh SY, et al. (2013) CGG repeat‐associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78 (3): 440–455.

van't Padje S, Engels B, Blonden L, et al. (2005) Characterisation of Fmrp in zebrafish: evolutionary dynamics of the fmr1 gene. Development Genes and Evolution 215 (4): 198–206.

Van Dam D, Errijgers V, et al. (2005) Cognitive decline, neuromotor and behavioural disturbances in a mouse model for fragile‐X‐associated tremor/ataxia syndrome (FXTAS). Behavioural Brain Research 162 (2): 233–239.

Verkerk AJ, de Graaff E, et al. (1993) Alternative splicing in the fragile X gene FMR1. Human Molecular Genetics 2 (4): 399–404.

Verkerk AJ, Pieretti M, et al. (1991) Identification of a gene (FMR‐1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65 (5): 905–914.

Wan L, Dockendorff TC, et al. (2000) Characterization of dFMR1, a Drosophila melanogaster homolog of the fragile X mental retardation protein. Molecular and Cellular Biology 20 (22): 8536–8547.

Wohrle D, Hennig I, et al. (1993) Mitotic stability of fragile X mutations in differentiated cells indicates early post‐conceptional trinucleotide repeat expansion. Nature Genetics 4 (2): 140–142.

Zhang Y, O'Connor JP, et al. (1995) The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2. EMBO Journal 14 (21): 5358–5366.

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.

Web Links

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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]