The molecular basis of the Fragile X syndrome


  • Harem Othman smail koya university



X-linked intellectual, FMR-1 triplet expansion region, RNA-binding protein, X mutation, DNA methylation, and Gene therapy


This analysis aimed to clarify the molecular basis of fragile X syndrome and explain the role of genetic material in the genetic disease's development and treatment. Fragile X syndrome is an X-linked mutation inheritance disorder. The mutated gene is called FMR-1. This is important for normal brain development and synaptic plasticity, which was verified and recognized in 1991, and this has become a hope for more clarification. FMR1 influences the translation of messenger RNA (mRNA), but identifying functional targets was complex and directly related to translational control and showed that dysregulated translation initiation signaling was observed for the FMR1 gene in the FMR1 knockout mouse model of FXS.

Because of the epigenetic alteration, such as hypermethylated at the DNA promoter region, and chromatin modification, such as H3K9 methylation, the FMR1 gene can be imprinted. Still, their mechanisms of aberrant epigenetic marks play a role in the etiology of many neurodevelopmental disorders, some of which we still do not fully understand and need to show more. The opportunities for epigenetic markers to map and alter epigenetic marks and the potential for therapies based on epigenetics and noncoding manipulation. For neurodevelopmental and behavioral conditions, including mental retardation, autism, anxiety, and mood disturbance, FMR1 loss of control is a model.

Most studies have focused on the new and effective approach for Fragile X syndrome, which is Gene therapy is unarguably the definitive way to treat and possibly cure genetic diseases. Many of them are under clinical trial, but more studies, such as the CRISPR/Cas9-based method, should be approved. Adeno-associated viral (AAV) vectors are highly effective for generating models. Most research is used in the mouse model of fragile X syndrome, where AAVs have been used to express fragile X mental retardation protein (FMRP), which is missing or highly reduced in the disorder. The vast expansions need southern blotting in myotonic dystrophy. Fragile X is diagnosed by a form of Southern blotting that relies on the size and the FRAXA gene's methylation status. Almost always, genetic testing is performed by PCR. The few Southern blotting uses include checking for significant destructive gene rearrangements and complete mutations of fragile X and myotonic dystrophy. Expansions suppress the expression of closely adjacent genes, causing loss of function. A named FMRI (fragile-X mental retardation syndrome) gene cDNA probe. Some unique molecular mechanisms, such as CGG expansion in Fragile-X syndrome, can make a particular sequence change in a gene far more probable than any other change.


 Abu Diab, M. and Eiges, R., 2019. The contribution of pluripotent stem cell (PSC)-based models to the study of fragile X syndrome (FXS). Brain sciences, 9(2), p.42.

 Bardoni, B. and Abekhoukh, S., 2014. CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome. Frontiers in cellular neuroscience, 8, p.81.

 Bartholomay, K.L., Lee, C.H., Bruno, J.L., Lightbody, A.A. and Reiss, A.L., 2019. Closing the gender gap in fragile X syndrome: review of females with fragile X syndrome and preliminary research findings. Brain Sciences, 9(1), p.11.

 Bhattacharya, A., Kaphzan, H., Alvarez-Dieppa, A.C., Murphy, J.P., Pierre, P. and Klann, E., 2012. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron, 76(2), pp.325-337.

 Biancalana, V., Glaeser, D., McQuaid, S. and Steinbach, P., 2015. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. European journal of human genetics, 23(4), pp.417-425.

 Boardman, F.K., 2020. Attitudes toward population screening among people living with fragile X syndrome in the UK:‘I wouldn't wish him away, I'd just wish his fragile X syndrome away'. Journal of Genetic Counseling.

 Braat, S. and Kooy, R.F., 2014. Fragile X syndrome neurobiology translates into rational therapy. Drug discovery today, 19(4), pp.510-519.

 Ciaccio, C., Fontana, L., Milani, D., Tabano, S., Miozzo, M. and Esposito, S., 2017. Fragile X syndrome: a review of clinical and molecular diagnoses. Italian journal of pediatrics, 43(1), p.39.

 Cordeiro, L., Ballinger, E., Hagerman, R. and Hessl, D., 2011. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. Journal of neurodevelopmental disorders, 3(1), pp.57-67.

 Cowley, B., Kirjanen, S., Partanen, J. and Castrén, M.L., 2016. Epileptic electroencephalography profile associates with attention problems in children with fragile X syndrome: review and case series. Frontiers in human neuroscience, 10, p.353.

 Crawford, D.C., Acuña, J.M. and Sherman, S.L., 2001. FMR1 and the fragile X syndrome: human genome epidemiology review. Genetics in Medicine, 3(5), pp.359-371.

 d’Hulst, C. and Kooy, R.F., 2009. Fragile X syndrome: from molecular genetics to therapy. Journal of medical genetics, 46(9), pp.577-584.

 De Geyter, C., M’Rabet, N., De Geyter, J., Zürcher, S., Moffat, R., Bösch, N., Zhang, H. and Heinimann, K., 2014. Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study. Genetics in medicine, 16(5), pp.374-378.

 Ding, Q., Sethna, F., Wu, X.T., Miao, Z., Chen, P., Zhang, Y., Xiao, H., Feng, W., Feng, Y., Li, X. and Wang, H., 2020. Transcriptome signature analysis repurposes trifluoperazine for the treatment of fragile X syndrome in mouse model. Communications Biology, 3(1), pp.1-13.

 Doherty, B.R., Longhi, E., Cole, V., Karmiloff-Smith, A., Cornish, K. and Scerif, G., 2020. Disentangling autism spectrum and attention-deficit/hyperactivity symptoms over development in fragile X syndrome. Research in Developmental Disabilities, p.103692.

 Doherty, T.S. and Roth, T.L., 2020. Epigenetics in Developmental Disorders. The Wiley Encyclopedia of Health Psychology, pp.75-81.

 Dölen, G., Osterweil, E., Rao, B.S., Smith, G.B., Auerbach, B.D., Chattarji, S. and Bear, M.F., 2007. Correction of fragile X syndrome in mice. Neuron, 56(6), pp.955-962.

 Gholizadeh, S., Arsenault, J., Xuan, I.C.Y., Pacey, L.K. and Hampson, D.R., 2014. Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice. Neuropsychopharmacology, 39(13), pp.3100-3111.

 Gigonzac, M.A.D., Teodoro, L.S., Minasi, L.B., Vieira, T.C. and da Cruz, A.D., 2016. Standardization of capillary electrophoresis for Diagnosis of fragile X syndrome in the Brazilian public health system. Electrophoresis, 37(23-24), pp.3076-3078.

 Gilbertson, K.E., Jackson, H.L., Dziuban, E.J., Sherman, S.L., Berry-Kravis, E.M., Erickson, C.A. and Valdez, R., 2019. Preventive care services and health behaviors in children with fragile X syndrome. Disability and health journal, 12(4), pp.564-573.

 Gold, B., Radu, D., Balanko, A. and Chiang, C.S., 2000. Diagnosis of Fragile X syndrome by Southern blot hybridization using a chemiluminescent probe: a laboratory protocol. Molecular Diagnosis, 5(3), pp.169-178.

 Gray, S.J., 2013. Gene therapy and neurodevelopmental disorders. Neuropharmacology, 68, pp.136-142.

 Greenblatt, E.J. and Spradling, A.C., 2018. Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins. Science, 361(6403), pp.709-712.

 Haebig, E., Sterling, A., Barton-Hulsey, A. and Friedman, L., 2020. Rates and predictors of co-occurring autism spectrum disorder in boys with fragile X syndrome. Autism & Developmental Language Impairments, 5, p.2396941520905328.

 Hagerman, P.J., 2012. Current gaps in understanding the molecular basis of FXTAS. Tremor and Other Hyperkinetic Movements, 2.

 Hagerman, R., Lauterborn, J., Au, J. and Berry-Kravis, E., 2012. Fragile X syndrome and targeted treatment trials. In Modeling fragile X syndrome (pp. 297-335). Springer, Berlin, Heidelberg.

 Hagerman, R.J., Des-Portes, V., Gasparini, F., Jacquemont, S. and Gomez-Mancilla, B., 2014. Translating molecular advances in fragile X syndrome into therapy: a review. The Journal of clinical psychiatry, 75(4), pp.294-307.

 Hall, S.S., Barnett, R.P. and Hustyi, K.M., 2016. Problem behaviour in adolescent boys with fragile X syndrome: relative prevalence, frequency and severity. Journal of intellectual disability research, 60(12), pp.1189-1199.

 Hampson, D.R., Hooper, A.W. and Niibori, Y., 2019. The application of Adeno-associated viral vector gene therapy to the treatment of fragile X syndrome. Brain Sciences, 9(2), p.32.

 Handt, M., Epplen, A., Hoffjan, S., Mese, K., Epplen, J.T. and Dekomien, G., 2014. Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening. Molecular and cellular probes, 28(5-6), pp.279-283.

 Hantash, F.M., Goos, D.M., Crossley, B., Anderson, B., Zhang, K., Sun, W. and Strom, C.M., 2011. FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States. Genetics in medicine, 13(1), pp.39-45.

 Hartley, S.L., Seltzer, M.M., Head, L. and Abbeduto, L., 2012. Psychological well‐being in fathers of adolescents and young adults with Down Syndrome, Fragile X syndrome, and autism. Family Relations, 61(2), pp.327-342.

 Hecht, M., Tabib, A., Kahan, T., Orlanski, S., Gropp, M., Tabach, Y., Yanuka, O., Benvenisty, N., Keshet, I. and Cedar, H., 2017. Epigenetic mechanism of FMR1 inactivation in Fragile X syndrome. International Journal of Developmental Biology, 61(3-4-5), pp.285-292.

 Henshall, D.C., 2020. Epigenetics and noncoding RNA: recent developments and future therapeutic opportunities. European Journal of Paediatric Neurology, 24, pp.30-34.

 Hoeffer, C.A., Sanchez, E., Hagerman, R.J., Mu, Y., Nguyen, D.V., Wong, H., Whelan, A.M., Zukin, R.S., Klann, E. and Tassone, F., 2012. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes, Brain and Behavior, 11(3), pp.332-341.

 Jacquemont, S., Berry-Kravis, E., Hagerman, R., Von Raison, F., Gasparini, F., Apostol, G., Ufer, M., Des Portes, V. and Gomez-Mancilla, B., 2014. The challenges of clinical trials in fragile X syndrome. Psychopharmacology, 231(6), pp.1237-1250.

 Jacquemont, S., Hagerman, R.J., Hagerman, P.J. and Leehey, M.A., 2007. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. The Lancet Neurology, 6(1), pp.45-55.

 -Jayaseelan, S. and Tenenbaum, S.A., 2012. Signalling pathways of fragile X syndrome. Nature, 492(7429), pp.359-360.

 Kidd, S.A., Lachiewicz, A., Barbouth, D., Blitz, R.K., Delahunty, C., McBrien, D., Visootsak, J. and Berry-Kravis, E., 2014. Fragile X syndrome: a review of associated medical problems. Pediatrics, 134(5), pp.995-1005.

 Kraan, C.M., Godler, D.E. and Amor, D.J., 2019. Epigenetics of fragile X syndrome and fragile X‐related disorders. Developmental Medicine & Child Neurology, 61(2), pp.121-127.

 Kronk, R., Bishop, E.E., Raspa, M., Bickel, J.O., Mandel, D.A. and Bailey Jr, D.B., 2010. Prevalence, nature, and correlates of sleep problems among children with fragile X syndrome based on a large scale parent survey. Sleep, 33(5), pp.679-687.

 Kumari, D. and Gazy, I., 2019. Towards Mechanism-Based Treatments for Fragile X Syndrome.

 Kumari, D. and Usdin, K., 2010. The distribution of repressive histone modifications on silenced FMR1 alleles provides clues to the mechanism of gene silencing in fragile X syndrome. Human molecular genetics, 19(23), pp.4634-4642.

 Kumari, D., Gazy, I. and Usdin, K., 2019. Pharmacological reactivation of the silenced FMR1 gene as a targeted therapeutic approach for fragile X syndrome. Brain sciences, 9(2), p.39.

 Kumari, D., Sciascia, N. and Usdin, K., 2020. Small Molecules Targeting H3K9 Methylation Prevent Silencing of Reactivated FMR1 Alleles in Fragile X Syndrome Patient Derived Cells. Genes, 11(4), p.356.

 Langberg, T., 2020. Excitability of Sensory Cortex in Mouse Models of Fragile X Syndrome and Autism Spectrum Disorders (Doctoral dissertation, UC Berkeley).

 Lee, B., Lee, K., Panda, S., Gonzales-Rojas, R., Chong, A., Bugay, V., Park, H.M., Brenner, R., Murthy, N. and Lee, H.Y., 2018. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nature Biomedical Engineering, 2(7), pp.497-507.

 Li, Y. and Jin, P., 2012. RNA-mediated neurodegeneration in fragile X-associated tremor/ataxia syndrome. Brain research, 1462, pp.112-117.

 Ligsay, A. and Hagerman, R.J., 2016. Review of targeted treatments in fragile X syndrome. Intractable & rare diseases research.

 Lyons, J.I., Kerr, G.R. and Mueller, P.W., 2015. Fragile X syndrome: scientific background and screening technologies. The Journal of Molecular Diagnostics, 17(5), pp.463-471.

 Maurin, T., Zongaro, S. and Bardoni, B., 2014. Fragile X syndrome: from molecular pathology to therapy. Neuroscience & Biobehavioral Reviews, 46, pp.242-255.

 Mazzocco, M.M., 2000. Advances in research on the fragile X syndrome. Mental retardation and developmental disabilities research reviews, 6(2), pp.96-106.

 McCary, L.M. and Roberts, J.E., 2013. Early identification of autism in fragile X syndrome: a review. Journal of Intellectual Disability Research, 57(9), pp.803-814.

 McMahon, M.A. and Cleveland, D.W., 2017. Gene-editing therapy for neurological disease. Nature Reviews Neurology, 13(1), pp.7-9.

 Mila, M., Alvarez‐Mora, M.I., Madrigal, I. and Rodriguez‐Revenga, L., 2018. Fragile X syndrome: An overview and update of the FMR1 gene. Clinical genetics, 93(2), pp.197-205.

 Mithal, D.S. and Chandel, N.S., 2020. Mitochondrial Dysfunction in Fragile-X Syndrome: Plugging the Leak May Save the Ship. Molecular Cell, 80(3), pp.381-383.

 Mulley, J.C., Yu, S., Gedeon, A.K., Donnelly, A., Turner, G., Loesch, D., Chapman, C.J., Gardner, R.J., Richards, R.I. and Sutherland, G.R., 1992. Experience with direct molecular Diagnosis of fragile X. Journal of medical genetics, 29(6), pp.368-374.

 Niu, M., Han, Y., Dy, A.B.C., Du, J., Jin, H., Qin, J., Zhang, J., Li, Q. and Hagerman, R.J., 2017. Fragile X syndrome: prevalence, treatment, and prevention in China. Frontiers in Neurology, 8, p.254.

 O'Donnell, W.T. and Warren, S.T., 2002. A decade of molecular studies of fragile X syndrome. Annual review of neuroscience, 25(1), pp.315-338.

 Rajaratnam, A., Shergill, J., Salcedo-Arellano, M., Saldarriaga, W., Duan, X. and Hagerman, R., 2017. Fragile X syndrome and fragile X-associated disorders. F1000Research, 6.

 Rattazzi, M.C., LaFauci, G. and Brown, W.T., 2004. Prospects for gene therapy in the fragile X syndrome. Mental retardation and developmental disabilities research reviews, 10(1), pp.75-81.

 Richter, J.D., Bassell, G.J. and Klann, E., 2015. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nature Reviews Neuroscience, 16(10), pp.595-605.

 Saldarriaga, W., Tassone, F., González-Teshima, L.Y., Forero-Forero, J.V., Ayala-Zapata, S. and Hagerman, R., 2014. Fragile X syndrome. Colombia medica, 45(4), pp.190-198.

 Salinas, R.D., Connolly, D.R. and Song, H., 2020. Invited Review: Epigenetics in neurodevelopment. Neuropathology and Applied Neurobiology, 46(1), pp.6-27.

 Santos, K.E., 1992. Fragile X syndrome: An educator's role in identification, prevention, and intervention. Remedial and Special Education, 13(2), pp.32-39.

 Sellier, C., Usdin, K., Pastori, C., Peschansky, V.J., Tassone, F. and Charlet-Berguerand, N., 2014. The multiple molecular facets of fragile X-associated tremor/ataxia syndrome. Journal of neurodevelopmental disorders, 6(1), pp.1-10.

 Sherman, S., Pletcher, B.A. and Driscoll, D.A., 2005. Fragile X syndrome: diagnostic and carrier testing. Genetics in Medicine, 7(8), pp.584-587.

 Shitik, E.M., Velmiskina, A.A., Dolskiy, A.A. and Yudkin, D.V., 2020. Reactivation of FMR1 gene expression is a promising strategy for fragile X syndrome therapy. Gene Therapy, pp.1-7.

 Siller, S.S. and Broadie, K., 2012. Matrix metalloproteinases and minocycline: therapeutic avenues for fragile X syndrome. Neural plasticity, 2012.

 Smail, H.O. and Mohamad, D.A., 2022. Identification DNA Methylation Change of ABCC8 Gene in Type 2 Diabetes Mellitus as Predictive Biomarkers. ARO-THE SCIENTIFIC JOURNAL OF KOYA UNIVERSITY, 10(1), pp.63-67.

 Smail, H.O. and Mohamad, D.A., 2022. Molecular Approaches for the Detection of DNA Methylation. Academic Journal of Nawroz University, 11(4), pp.452-463.

 Smail, H.O., 2016. Qualitative and Quantitative Identification of DNA Methylation Changes in Blood of the Breast Cancer patients (,MSC thesis, University of Sulaimani).

 Smail, H.O., 2019. The epigenetics of diabetes, obesity, overweight and cardiovascular disease. AIMS genetics, 6(03), pp.036-045.

 Sofocleous, C., Kolialexi, A. and Mavrou, A., 2009. Molecular Diagnosis of Fragile X syndrome. Expert review of molecular diagnostics, 9(1), pp.23-30.

 Sutherland, G.R., Gedeon, A., Kornman, L., Donnelly, A., Byard, R.W., Mulley, J.C., Kremer, E., Lynch, M., Pritchard, M., Yu, S. and Richards, R.I., 1991. Prenatal Diagnosis of fragile X syndrome by direct detection of the unstable DNA sequence. New England Journal of Medicine, 325(24), pp.1720-1722.

 Tabolacci, E. and Chiurazzi, P., 2013. Epigenetics, fragile X syndrome and transcriptional therapy. American journal of medical genetics Part A, 161(11), pp.2797-2808.

 Tabolacci, E., Pomponi, M.G., Remondini, L., Pietrobono, R., Nobile, V., Pennacchio, G., Gurrieri, F., Neri, G., Genuardi, M. and Chiurazzi, P., 2020. Methylated premutation of the FMR1 gene in three sisters: correlating CGG expansion and epigenetic inactivation. European Journal of Human Genetics, 28(5), pp.567-575.

 Tassone, F., 2015. Advanced technologies for the molecular Diagnosis of fragile X syndrome. Expert review of molecular diagnostics, 15(11), pp.1465-1473.

 Tejada, M.I., 2001. Prevention of fragile X syndrome by prenatal genetic Diagnosis: advantages and controversial aspects. Revista de Neurologia, 33, pp.S14-9.

 Verkerk, A.J., Pieretti, M., Sutcliffe, J.S., Fu, Y.H., Kuhl, D.P., Pizzuti, A., Reiner, O., Richards, S., Victoria, M.F., Zhang, F. and Eussen, B.E., 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), pp.905-914.

 Visootsak, J., Warren, S.T., Anido, A. and Graham Jr, J.M., 2005. Fragile X syndrome: an update and review for the primary pediatrician. Clinical Pediatrics, 44(5), pp.371-381.

 Wang, L.W., Berry-Kravis, E. and Hagerman, R.J., 2010. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics, 7(3), pp.264-274.

 Wang, T., Bray, S.M. and Warren, S.T., 2012. New perspectives on the biology of fragile X syndrome. Current opinion in genetics & development, 22(3), pp.256-263.

 Westmark, C.J., Kniss, C., Sampene, E., Wang, A., Milunovich, A., Elver, K., Hessl, D., Talboy, A., Picker, J., Haas-Givler, B. and Esler, A., 2020. Soy-Based Infant Formula is Associated with an Increased Prevalence of Comorbidities in Fragile X Syndrome. Nutrients, 12(10), p.3136.

 Wijetunge, L.S., Chattarji, S., Wyllie, D.J. and Kind, P.C., 2013. Fragile X syndrome: from targets to treatments. Neuropharmacology, 68, pp.83-96.

 Wolff, J.J., Bodfish, J.W., Hazlett, H.C., Lightbody, A.A., Reiss, A.L. and Piven, J., 2012. Evidence of a distinct behavioral phenotype in young boys with fragile X syndrome and autism. Journal of the American Academy of Child & Adolescent Psychiatry, 51(12), pp.1324-1332.

 Yrigollen, C.M., Durbin-Johnson, B., Gane, L., Nelson, D.L., Hagerman, R., Hagerman, P.J. and Tassone, F., 2012. AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genetics in medicine, 14(8), pp.729-736.

 Yudkin, D., Hayward, B.E., Aladjem, M.I., Kumari, D. and Usdin, K., 2014. Chromosome fragility and the abnormal replication of the FMR1 locus in fragile X syndrome. Human molecular genetics, 23(11), pp.2940-2952.

 Zhao, X. and Bhattacharyya, A., 2020. Advances in Human Stem Cells and Genome Editing to Understand and Develop Treatment for Fragile X Syndrome. In Neurodevelopmental Disorders (pp. 33-53). Springer, Cham.

 Zhou, Y., Lum, J.M., Yeo, G.H., Kiing, J., Tay, S.K. and Chong, S.S., 2006. Simplified molecular Diagnosis of fragile X syndrome by fluorescent methylation-specific PCR and GeneScan analysis. Clinical Chemistry, 52(8), pp.1492-1500.


2023-05-08 — Updated on 2023-09-18

How to Cite

smail, H. O. (2023). The molecular basis of the Fragile X syndrome. Journal of Experimental and Molecular Biology, 24(2), 131–144.