The class X-associated spectrum disorders (FXSD) combines the following clinical syndromes: fragile X chromosome-linked mental retardation syndrome (fragile X syndrome, FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and a group of neuropsychiatric disorders (fragile X-associated neuropsychiatric disorders, FXAND). These syndromes occur as a result of dynamic mutations of the FMR1 gene caused by expansion of trinucleotide repeats in the gene promoter. FXS syndrome (mental retardation, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD)) occurs when the FMR1 gene is completely mutated (an increase in the number of CGG repeats to more than 200), which is accompanied by full or partial suppression of FMRP protein expression. The clinical manifestations of FXTAS, FXPOI, and FXAND can occur in individuals carrying the FMR1 premutation (CGG repeats in the range 55–200). The main pathogenetic mechanisms of these diseases include a decrease in FMRP expression and accumulation of FMR1 mRNA containing an increased number of repeats. This review analyzes genophenotypic relationships within the spectrum of conditions associated with FMR1 dynamic mutations. An analysis of the relationship between the molecular mechanisms (FMRP defi ciency, translation of atypical isoforms, increased function of FMR1 mRNA) and clinical manifestations (level of cognitive development, severity of ASD, severity of symptoms of FXTAS, FXPOI and FXAND)is presented.
Similar content being viewed by others
References
Abitbol, M., Menini, C., Delezoide, A.-L., et al., “Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain,” Nat. Genet., 4, 147–153 (1993).
Allen, E. G., Sullivan, A. K., Marcus, M., et al., “Examination of reproductive aging milestones among women who carry the FMR1 premutation,” Hum. Reprod., 22, No. 8, 2142–2152 (2007).
Antar, L. N., Li, C., Zhang, H., et al., “Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses,” Mol. Cell. Neurosci., 32, 37–48 (2006).
Arocena, D. G., Iwahashi, C. K., Won, N., et al., “Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells,” Hum. Mol. Genet., 14, 3661–3671 (2005).
Arpone, M., Baker, E. K., Bretherton, L., et al., “Intragenic DNA methylation in buccal epithelial cells and intellectual functioning in a paediatric cohort of males with fragile X,” Sci. Rep., 8, No. 1, 3644 (2018).
Ascano, M., Jr., Mukherjee, N., Bandaru, P., et al., “FMRP targets distinct mRNA sequence elements to regulate protein expression,” Nature, 492, 382–386 (2012).
Ashwood, P., Nguyen, D. V., Hessl, D., et al., “Plasma cytokine profiles in Fragile X subjects: is there a role for cytokines in the pathogenesis?” Brain Behav. Immun., 24, No. 6, 898–902 (2010).
Bailey, D., B., Jr., Raspa, M., Olmsted, M., and Holiday, D. B., “Cooccurring conditions associated with FMR1 gene variations: findings from a national parent survey,” Am. J. Med. Genet., 146A, No. 16, 2060–2069 (2008).
Baker, E. K., Arpone, M., Aliaga, S. M., et al., “Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features,” Mol. Autism, 3, 10–21 (2019).
Baker, E. K., Arpone, M., Kraan, C., et al., “FMR1 mRNA from full mutation alleles is associated with ABC-CFX scores in males with fragile X syndrome,” Sci. Rep., 10, No. 1, 11701 (2020).
Baron-Cohen, S., Ring, H. A., Bullmore, E. T., et al., “The amygdala theory of autism,” Neurosci. Biobehav. Rev., 24, No. 3, 355–364 (2000).
Basuta, K., Schneider, A., Gane, L., et al., “High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome,” Am. J. Med. Genet., 167A, No. 9, 2154–2161 (2015).
Bechara, E. G., Didiot, M. C., Melko, M., et al., “A novel function for fragile X mental retardation protein in translational activation,” PLoS Biol., 7, E16–E16 (2009).
Berman, R. F., Buijsen, R. A., Usdin, K., et al., “Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome,” J. Neurodev. Disord., 6, No. 1, 25 (2014).
Berry-Kravis, E., Potanos, K., Weinberg, D., et al., “Fragile X-associated tremor/ataxia syndrome in sisters related to X-inactivation,” Ann. Neurol., 57, 144–147 (2005).
Brown, M. R., Kronengold, J., Gazula, V. R., et al., “Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack,” Nat. Neurosci., 13, 819–821 (2010).
Budimirovic, D. B. and Kaufmann, W. E., “What can we learn about autism from studying fragile X syndrome?” Dev. Neurosci., 33, No. 5, 379–394 (2011).
Budimirovic, D. B. and Subramanian, M., “Neurobiology of autism and intellectual Disability: fragile X syndrome,” in: Neurobiology of Disease, Johnston, M. et al. (eds.), Oxford University Press, London (2016), 2nd ed.
Buijsen, R. A., Visser, J. A., Kramer, P., et al., “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,” Hum. Reprod., 31, No. 1, 158–168 (2016).
Clifford, S., Dissanayake, C., Bui, Q. M., et al., “Autism spectrum phenotype in males and females with fragile X full mutation and premutation,” J. Autism Dev. Disord., 37, No. 4, 738–747 (2007).
Cohen, S., Masyn, K., Adams, J., et al., “Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome,” Neurology, 67, No. 8, 1426–1431 (2006).
Colak, D., Zaninovic, N., Cohen, M. S., et al., “Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome,” Science, 343, No. 6174, 1002–1005 (2014).
Cornish, K. M., Kogan, C. S., Li, L., et al., “Lifespan changes in working memory in fragile X premutation males,” Brain Cogn., 69, No. 3, 551–558 (2009).
Cornish, K. M., Kraan, C. M., Bui, Q. M., et al., “Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women,” Neurology, 84, No. 16, 1631–1638 (2015).
de Vries, B. B., Wiegers, A. M., Smits, A. P., et al., “Mental status of females with an FMR1 gene full mutation,” Am. J. Hum. Genet., 58, No. 5, 1025–1032 (1996).
Dean, D. D., Agarwal, S., and Muthuswamy, S., “Defi ning the role of FMR1 gene in unexplained recurrent spontaneous abortion,” J. Assist. Reprod. Genet., 36, No. 11, 2245–2250 (2019).
DeMarco, B., Stefanovic, S., Williams, A., et al., “FMRP – G-quadruplex mRNA – miR-125a interactions: Implications for miR-125a mediated translation regulation of PSD-95 mRNA,” PLoS One, 14, No. 5, e0217275 (2019).
Didiot, M. C., Tian, Z., Schaeffer, C., et al., “The G-quartet containing FMRP binding site in FMR1 mRNA is a potent exonic splicing enhancer,” Nucleic Acids Res., 36, 4902–4912 (2008).
Doll, C. A., Yergert, K. M., and Appel, B. H., “The RNA binding protein fragile X mental retardation protein promotes myelin sheath growth,” Glia, 68, No. 3, 495–508 (2020).
Drouin, R., Angers, M., Dallaire, N., et al., “Structural and functional characterization of the human FMR1 promoter reveals similarities with the hnRNP-A2 promoter region,” Hum. Mol. Genet., 6, 2051–2060 (1997).
Ennis, S., Ward, D., and Murray, A., “Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers,” Eur. J. Hum. Genet., 14, No. 2, 253–255 (2006).
Farzin, F., Perry, H., Hessl, D., et al., “Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation,” J. Dev. Behav. Pediatr., 27, No. 2 Suppl., 137–144 (2006), PMID: 16685180, https://doi.org/10.1097/00004703-200604002-00012.
Field, M., Dudding-Byth, T., Arpone, M., et al., “Significantly elevated FMR1 mRNA and mosaicism for methylated premutation and full mutation alleles in two brothers with autism features referred for fragile X testing,” Int. J. Mol. Sci., 20, No. 16, 3907 (2019).
Friedman-Gohas, M., Elizur, S. E., Dratviman-Storobinsky, O., et al., “FMRpolyG accumulates in FMR1 premutation granulosa cells,” J. Ovarian Res., 13, No. 1, 22 (2020).
Gallego, P. K., Burris, J. L., and Rivera, S. M., “Visual motion processing deficits in infants with the fragile X premutation,” J. Neurodev. Disord., 6, No. 1, 29 (2014), https://doi.org/10.1186/1866-1955-6-29.
Garcia-Alegria, E., Ibáñez, B., Mínguez, M., et al., “Analysis of FMR1 gene expression in female premutation carriers using robust segmented linear regression models,” RNA, 13, No. 5, 756–762 (2007).
Godler, D. E., “Treatment and diagnosis of epigenetic disorders and conditions,” Google Patents (2012).
Godler, D. E., Slater, H. R., Bui, Q. M., et al., “FMR1 intron 1 methylation predicts FMRP expression in blood of female carriers of expanded FMR1 alleles,” J. Mol. Diagn., 13, No. 5, 528–536 (2011).
Godler, D. E., Slater, H. R., Bui, Q. M., et al., “Fragile X mental retardation 1 (FMR1) intron 1 methylation in blood predicts verbal cognitive impairment in female carriers of expanded FMR1 alleles: evidence from a pilot study,” Clin. Chem., 58, No. 3, 590–598 (2012).
Godler, D. E., Tassone, F., Loesch, D. Z., et al., “Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio,” Hum. Mol. Genet., 19, No. 8, 1618–1632 (2010).
Greco, C. M., Berman, R. F., Martin, R. M., et al., “Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS),” Brain, 129, Pt. 1, 243–255 (2006).
Hagerman, P. J. and Hagerman, R. J., “The fragile-X premutation: a maturing perspective,” Am. J. Hum. Genet., 74, No. 5, 805–816 (2004).
Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., et al., “Fragile X syndrome,” Nat. Rev. Dis. Primers, 3, 17065 (2017).
Hagerman, R. J., Hull, C. E., Safanda, J. F., et al., “High functioning fragile X males: demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression,” Am. J. Med. Genet., 51, No. 4, 298–308 (1994).
Hagerman, R. J., Protic, D., Rajaratnam, A., et al., “Fragile X-associated neuropsychiatric disorders (FXAND),” Front. Psychiatry, 9, 564 (2018).
Hall, D. A., Nag, S., Ouyang, B., et al., “Fragile X gray zone alleles are associated with signs of parkinsonism and earlier death,” Mov. Disord., 35, No. 8, 1448–1456 (2020).
Hall, D. A., Robertson-Dick, E. E., O’Keefe, J. A., et al., “X-inactivation in the clinical phenotype of fragile X premutation carrier sisters,” Neurol. Genet., 2, No. 1, e45 (2016).
Hall, D., Pickler, L., Riley, K., et al., “Parkinsonism and cognitive decline in a fragile X mosaic male,” Mov. Disord., 25, No. 10, 1523–1524 (2010).
Hashimoto, R. I., Backer, K. C., Tassone, F., et al., “An fMRI study of the prefrontal activity during the performance of a working memory task in premutation carriers of the fragile X mental retardation 1 gene with and without fragile X-associated tremor/ataxia syndrome (FX-TAS),” J. Psychiatr. Res., 45, No. 1, 36–43 (2010).
Hatton, D. D., Sideris, J., Skinner, M., et al., “Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP,” Am. J. Med. Genet. A, 140A, No. 17, 1804–1813 (2006).
Heine-Suñer, D., Torres-Juan, L., Morlà, M., et al., “Fragile-X syndrome and skewed X-chromosome inactivation within a family: a female member with full inactivation of the functional X chromosome,” Am. J. Med. Genet. A, 122A, No. 2, 108–114 (2003).
Hessl, D., Dyer-Friedman, J., Glaser, B., et al., “The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome,” Pediatrics, 108, No. 5, E88 (2001).
Hessl, D., Nguyen, D. V., Green, C., et al., “A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome,” J. Neurodev. Disord., 1, No. 1, 33–45 (2009).
Hessl, D., Tassone, F., Loesch, D. Z., et al., “Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation,” Am. J. Med. Genet. B, Neuropsychiatr. Genet., 139B, No. 1, 115–121 (2005).
Hinds, H. L., Ashley, C. T., Sutcliffe, J. S., et al., “Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome,” Nat. Genet., 3, No. 1, 36–43 (1993).
Hukema, R. K., Buijsen, R. A., Schonewille, M., et al., “Reversibility of neuropathology and motor defi cits in an inducible mouse model for FXTAS,” Hum. Mol. Genet., 24, No. 17, 4948–4957 (2015).
Jacquemont, S., Hagerman, R. J., Leehey, M. A., et al., “Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population,” JAMA, 291, No. 4, 460–469 (2004).
Jacquemont, S., Leehey, M. A., Hagerman, R. J., et al., “Size bias of fragile X premutation alleles in late-onset movement disorders,” J. Med. Genet., 43, No. 10, 804–809 (2006).
Jalnapurkar, I., Rafika, N., Tassone, F., and Hagerman, R., “Immune mediated disorders in women with a fragile X expansion and FXTAS,” Am. J. Med. Genet. A., 167A, No. 1, 190–7 (2015).
Jiraanont, P., Kumar, M., Tang, H. T., et al., “Size and methylation mosaicism in males with Fragile X syndrome,” ExpertRev. Mol. Diagn., 17, No. 11, 1023–1032 (2017a).
Jiraanont, P., Sweha, S. R., AlOlaby, R. R., et al., “Clinical and molecular correlates in fragile X premutation females,” eNeurologicalSci, 7, 49–56 (2017b).
Kenna, H. A., Tartter, M., and Hall, S. S., “High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene,” Am. J. Med. Genet. B, Neuropsychiatr. Genet., 162, No. 8, 872–878 (2013).
Kenny, P. J., Zhou, H., Kim, M., et al., “MOV10 and FMRP regulate AGO2 association with microRNA recognition elements,” Cell Rep., 9, 1729–1741 (2014).
Kim, K., Hessl, D., Randol, J. L., et al., “Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions,” PLoS One, 14, No. 12, e0226811 (2019).
Kim, M., Bellini, M., and Ceman, S., “Fragile X mental retardation protein FMRP binds mRNAs in the nucleus,” Mol. Cell. Biol., 29, 214–228 (2009).
Kirchgessner, C. U., Warren, S. T., and Willard, H. F., “X inactivation of the FMR1 fragile X mental retardation gene,” J. Med. Genet., 32, No. 12, 925–929 (1995).
Kover, S. T., Pierpont, E. I., Kim, J. S., et al., “A neurodevelopmental perspective on the acquisition of nonverbal cognitive skills in adolescents with fragile X syndrome,” Dev. Neuropsychol., 38, No. 7, 445–460 (2013).
Kraan, C. M., Godler, D. E., and Amor, D. J., “Epigenetics of fragile X syndrome and fragile X-related disorders,” Dev. Med. Child Neurol., 61, No. 2, 121–127 (2019).
Krans, A., Kearse, M. G., and Todd, P. K., “Repeat-associated nonAUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome,” Ann. Neurol., 80, 871–881 (2016).
Kumari, D. and Usdin, K., “Interaction of the transcription factors USF1, USF2, and α-Pal/Nrf-1 with the FMR1 promoter. Implications for fragile X mental retardation syndrome,” J. Biol. Chem., 276, 4357–4364 (2001).
Lachiewicz, A., Dawson, D., and Spiridigliozzi, G., “Indicators of anxiety and depression in women with the fragile X premutation: assessment of a clinical sample,” J. Intellect. Disabil. Res., 54, No. 7, 597–610 (2010).
Leehey, M. A., Berry-Kravis, E., Goetz, C. G., et al., “FMR1 CGG repeat length predicts motor dysfunction in premutation carriers,” Neurology, 70, No. 16, Pt. 2, 1397–402 (2008).
Loesch, D. and Hagerman, R., “Unstable mutations in the FMR1 gene and the phenotypes,” Adv. Exp. Med. Biol., 769, 78–114 (2012), https://doi.org/10.1007/978-1-4614-5434-2_6.
Loesch, D. Z., Bui, M. Q., and Hammersley, E., “Psychological status in female carriers of premutation FMR1 allele showing a complex relationship with the size of CGG expansion,” Clin. Genet., 87, No. 2, 173–178 (2015).
Loesch, D. Z., Bui, Q. M., Dissanayake, C., et al., “Molecular and cognitive predictors of the continuum of autistic behaviours in fragile, X,” Neurosci. Biobehav. Rev., 31, No. 3, 315–326 (2007).
Loesch, D. Z., Churchyard, A., Brotchie, P., et al., “Evidence for, and a spectrum of, neurological involvement in carriers of the fragile X premutation: FXTAS and beyond,” Clin. Genet., 67, 412–417 (2005).
Loesch, D. Z., Godler, D. E., Evans, A., et al., “Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism,” Genet. Med., 13, 392–399 (2011).
Loesch, D. Z., Huggins, R. M., and Hagerman, R. J., “Phenotypic variation and FMRP levels in fragile X,” Ment. Retard. Dev. Disabil. Res. Rev., 10, No. 1, 31–41 (2004).
Loesch, D. Z., Sherwell, S., Kinsella, G., et al., “Fragile X-associated tremor/ataxia phenotype in a male carrier of unmethylated full mutation in the FMR1 gene,” Clin. Genet., 82, No. 1, 88–92 (2012).
Loesch, D. Z., Tassone, F., Mellick, G. D., et al., “Evidence for the role of FMR1 gray zone alleles as a risk factor for parkinsonism in females,” Mov. Disord., 33, No. 7, 1178–1181 (2018).
Lozano, R., Rosero, C., and Hagerman, R., “Fragile X spectrum disorders,” Intractable Rare Dis. Res., 3, No. 4, 134–146 (2014).
Ludwig, A. L., Espinal, G. M., Pretto, D., et al., “CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size,” Hum. Mol. Genet., 23, 3228–3238 (2014).
Mailick, M. R., Hong, J., Greenberg, J., et al., “Curvilinear association of CGG repeats and age at menopause in women with FMR1 premutation expansions,” Am. J. Med. Genet. B Neuropsychiatr. Genet., 165B, No. 8, 705–711 (2014).
Mankodi, A. and Thornton, C. A., “Myotonic syndromes,” Curr. Opin. Neurol., 15, 545–552 (2002).
McDuffie, A., Abbeduto, L., Lewis, P., et al., “Autism spectrum disorder in children and adolescents with fragile X syndrome: within-syndrome differences and age-related changes,” Am. J. Intellect. Dev. Disabil., 115, No. 4, 307–326 (2010).
Moore, C. J., Daly, E. M., Schmitz, N., et al., “A neuropsychological investigation of male premutation carriers of fragile X syndrome,” Neuropsychologia, 42, 1934–1947 (2004).
Myrick, L. K., Deng, P. Y., Hashimoto, H., et al., “Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures,” Proc. Natl. Acad. Sci. USA, 112, 949–956 (2015).
Naumann, A., Hochstein, N., Weber, S., et al., “A distinct DNA-methylation boundary in the 5□-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome,” Am. J. Hum. Genet., 85, 606–616 (2009).
Nelson, L. M., Covington, S. N., and Rebar, R. W., “An update: spontaneous premature ovarian failure is not an early menopause,” Fertil. Steril., 283, 1327–1332 (2005).
Nolin, S. L., Glicksman, A., and Houck, G. E., Jr., et al., “Mosaicism in fragile X affected males,” Am. J. Med. Genet., 51, No. 4, 509–512 (1994).
Pastori, C., Peschansky, V. J., Barbouth, D., et al., “Comprehensive analysis of the transcriptional landscape of the human FMR1 gene reveals two new long noncoding RNAs differentially expressed in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome,” Hum. Genet., 133, 59–67 (2014).
Peprah, E., He, W., Allen, E., et al., “Examination of FMR1 transcript and protein levels among 74 premutation carriers,” J. Hum. Genet., 55, No. 1, 66–68 (2010).
Pereverzeva, D. S., Danilina, K. K., and Gorbachevskaya, N. L., “General and specific mechanisms of impairments to the development of visual cognitive functions in people with defi ciency of FMRP protein,” Zh. Vyssh. Nerv. Deyat., 65, No. 3, 259–270 (2015).
Pereverzeva, D. S., Tyushkevich, S. A., Gorbachevskaya, N. L., et al., “Heterogeneity of the clinical picture in syndromes associated with dynamic mutations in the FMR1 gene,” Zh. Nevrol. Psikhiatr., 119, No. 7, 103–111 (2019).
Peschansky, V. J., Pastori, C., Zeier, Z., et al., “The long noncoding RNA FMR4 promotes proliferation of human neural precursor cells and epigenetic regulation of gene expression in trans,” Mol. Cell. Neurosci., 74, 49–57 (2016).
Pietrobono, R., Pomponi, M. G., Tabolacci, E., et al., “Quantitative analysis of DNA demethylation and transcriptional reactivation of the FMR1 gene in fragile X cells treated with 5 azadeoxycytidine,” Nucleic Acids Res., 30, 3278–3285 (2002).
Pretto, D. I., Hunsaker, M. R., Cunningham, C. L., et al., “Intranuclear inclusions in a fragile X mosaic male,” Transl. Neurodegener., 2, No. 1, 10 (2013).
Pretto, D. I., Mendoza-Morales, G., Lo, J., et al., “CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles,” J. Med. Genet., 51, No. 5, 309–318 (2014b).
Pretto, D., Yrigollen, C. M., Tang, H. T., et al., “Clinical and molecular implications of mosaicism in FMR1 full mutations,” Front. Genet., 5, 318 (2014a).
Rajaratnam, A., Shergill, J., Salcedo-Arellano, M., et al., “Fragile X syndrome and fragile X-associated disorders,” F1000Res, 6, 2112 (2017).
Raspa, M., Wylie, A., Wheeler, A. C., et al., “Sensory difficulties in children with an FMR1 premutation,” Front. Genet., 9, 351 (2018), PMID: 30233641, PMCID: PMC6127619, https://doi.org/10.3389/fgene.2018.00351.
Roberts, J. E., Bailey, D. B., and Mankowski, J., “Mood and anxiety disorders in females with the FMR1 premutation,” Am. J. Med. Genet. B Neuropsychiatr. Genet., 150, No. 1, 130–139 (2009).
Roberts, J. E., Ezell, J. E., Fairchild, A. J., et al., “Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder,” Am. J. Med. Genet. B Neuropsychiatr. Genet., 177, No. 7, 665–675 (2018).
Rodriguez-Revenga, L., Madrigal, I., Badenas, C., et al., “Premature ovarian failure and fragile X female premutation carriers: no evidence for a skewed X-chromosome inactivation pattern,” Menopause, 16, No. 5, 944–949 (2009a).
Rodriguez-Revenga, L., Madrigal, I., Pagonabarraga, J., et al., “Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families,” Eur. J. Hum. Genet., 17, No. 10, 1359–1362 (2009b).
Rousseau, F., Heitz, D., Biancalana, V., et al., “Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation,” New Engl. J. Med., 325, No. 24, 1673–1681 (1991).
Salcedo-Arellano, M. J., Dufour, B., McLennan, Y., et al., “Fragile X syndrome and associated disorders: Clinical aspects and pathology,” Neurobiol. Dis., 136, 104740(2020).
Santa María, L., Pugin, A., Alliende, M. A., et al., “FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile,” Clin. Genet., 86, No. 4, 378–382 (2014).
Schneider, A., Johnston, C., and Tassone, F., “Broad autism spectrum and obsessive-compulsive symptoms in adults with the fragile X premutation,” Clin. Neuropsychol., 30, No. 6, 929–943 (2016).
Sellier, C., Buijsen, R. A. M., He, F., et al., “Translation of Expanded CGG Repeats into FMRpolyG is pathogenic and may contribute to fragile X tremor ataxia syndrome,” Neuron, 93, No. 2, 331–347 (2017).
Sellier, C., Usdin, K., Pastori, C., et al., “The multiple molecular facets of fragile X-associated tremor/ataxia syndrome,” J. Neurodev. Disord., 6, No. 1, 23 (2014).
Sharma, A., Hoeffer, C. A., Takayasu, Y., et al., “Dysregulation of mTOR signaling in fragile X syndrome,” J. Neurosci., 30, No. 2, 694–702 (2010).
Shelton, A. L., Cornish, K. M., Godler, D., et al., “White matter microstructure, cognition, and molecular markers in fragile X premutation females,” Neurology, 88, No. 22, 2080–2088 (2017).
Sherman, S. L., “Premature ovarian failure in the fragile X syndrome,” Am. J. Med. Genet., 97, No. 3, 189–194 (2000).
Sterling, A. and Abbeduto, L., “Language development in school-age girls with fragile X syndrome,” J. Intellect. Disabil. Res., 56, No. 10, 974–983 (2012).
Stöger, R., Genereux, D. P., Hagerman, R. J., et al., “Testing the FMR1 promoter for mosaicism in DNA methylation among CpG sites, strands, and cells in FMR1-expressing males with fragile X syndrome,” PLoS One, 6, No. 8, e23648 (2011).
Sullivan, A. K., Marcus, M., Epstein, M. P., et al., “Association of FMR1 repeat size with ovarian dysfunction,” Hum. Reprod., 20, 402–412 (2005).
Tassone, F., Beilina, A., Carosi, C., et al., “Elevated FMR1 mRNA in premutation carriers is due to increased transcription,” RNA, 13, No. 4, 555–562 (2007).
Tassone, F., Hagerman, R. J., Chamberlain, W. D., and Hagerman, P. J., “Transcription of the FMR1 gene in individuals with fragile X syndrome,” Am. J. Med. Genet., 97, No. 3, 195–203 (2000).
Tassone, F., Hagerman, R. J., Taylor, A. K., and Hagerman, P. J., “A majority of fragile X males with methylated, full mutation alleles have significant levels of FMR1 messenger RNA,” J. Med. Genet., 38, No. 7, 453–456 (2001).
Tassone, F., Iong, K. P., Tong, T. H., et al., “FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States,” Genome Med., 4, No. 12, 100 (2012), https://doi.org/10.1186/gm401.
Tassone, F., Iwahashi, C., and Hagerman, P. J., “FMR1 RNA within the intranuclear inclusions of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS),” RNA Biol., 1, No. 2, 103–105 (2004).
Todd, P. K., Oh, S. Y., Krans, A., et al., “CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome,” Neuron, 78, No. 3, 440–455 (2013).
Tyushkevich, S. A., Voinova, V. Yu., Yurov, I. Yu., and Gorbachevskaya, N. L., “The nature of cognitive impairments in children with mental retardation associated with fragile X chromosome,” Defektologiya, 3, 29–37 (2010).
Villate, O., Ibarluzea, N., Maortua, H., et al., “Effect of AGG interruptions on FMR1 maternal transmissions,” Front. Mol. Biosci., 7, 135 (2020).
Welt, C. K., Smith, P. C., and Taylor, A. E., “Evidence of early ovarian aging in fragile X premutation carriers,” J. Clin. Endocrinol. Metab., 89, No. 9, 4569–4574 (2004).
Westmark, C. J., Sokol, D. K., Maloney, B., and Lahiri, D. K., “Novel roles of amyloid-beta precursor protein metabolites in fragile X syndrome and autism,” Mol. Psychiatry, 21, No. 10, 1333–1341 (2016).
Wheeler, A. C., Sideris, J., Hagerman, R., et al., “Developmental profiles of infants with an FMR1 premutation,” J. Neurodev. Disord., 8, No. 40 (2016), https://doi.org/10.1186/s11689-016-9171-8.
Yudkin, D. V., Lemskaya, N. A., Grishchenko, I. V., and Dol’skii, A. A., “Changes in chromatin composition on expansion of the CGG trinucleotide repeat in the FMR1 gene,” Mol. Biol. (Mosk.), 49, No. 2, 205–211 (2015).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 72, No. 3, pp. 293–316, May–June, 2022.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Pereverzeva, D.S., Tyushkevich, S.A., Ulas, E.V. et al. Spectrum of Syndromal Disorders Associated with Expansion of CGG Repeats of the FMR1 Gene Promoter: Pathogenetic Mechanisms and Clinical Manifestations. Neurosci Behav Physi 52, 1385–1400 (2022). https://doi.org/10.1007/s11055-023-01371-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11055-023-01371-2