Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

doi:10.3389/fncel.2021.764761

Review

. 2021 Nov 19:15:764761.

doi: 10.3389/fncel.2021.764761. eCollection 2021.

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Snow Bach^{1

2}, Stephen Shovlin², Michael Moriarty³, Barbara Bardoni⁴, Daniela Tropea^{2

5

6}

Affiliations

¹ School of Mathematical Sciences, Dublin City University, Dublin, Ireland.
² Neuropsychiatric Genetics, Department of Psychiatry, School of Medicine, Trinity College Dublin, Trinity Translational Medicine Institute, St James's Hospital, Dublin, Ireland.
³ School of Medicine, Trinity College Dublin, Dublin, Ireland.
⁴ Inserm, CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, Université Côte d'Azur, Valbonne, France.
⁵ Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁶ FutureNeuro, The SFI Research Centre for Chronic and Rare Neurological Diseases, Dublin, Ireland.

PMID: 34867203
PMCID: PMC8640214
DOI: 10.3389/fncel.2021.764761

Review

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Snow Bach et al. Front Cell Neurosci. 2021.

. 2021 Nov 19:15:764761.

doi: 10.3389/fncel.2021.764761. eCollection 2021.

Authors

Snow Bach^{1

2}, Stephen Shovlin², Michael Moriarty³, Barbara Bardoni⁴, Daniela Tropea^{2

5

6}

Affiliations

¹ School of Mathematical Sciences, Dublin City University, Dublin, Ireland.
² Neuropsychiatric Genetics, Department of Psychiatry, School of Medicine, Trinity College Dublin, Trinity Translational Medicine Institute, St James's Hospital, Dublin, Ireland.
³ School of Medicine, Trinity College Dublin, Dublin, Ireland.
⁴ Inserm, CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, Université Côte d'Azur, Valbonne, France.
⁵ Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁶ FutureNeuro, The SFI Research Centre for Chronic and Rare Neurological Diseases, Dublin, Ireland.

PMID: 34867203
PMCID: PMC8640214
DOI: 10.3389/fncel.2021.764761

Abstract

Rett syndrome (RTT) and Fragile X syndrome (FXS) are two monogenetic neurodevelopmental disorders with complex clinical presentations. RTT is caused by mutations in the Methyl-CpG binding protein 2 gene (MECP2) altering the function of its protein product MeCP2. MeCP2 modulates gene expression by binding methylated CpG dinucleotides, and by interacting with transcription factors. FXS is caused by the silencing of the FMR1 gene encoding the Fragile X Mental Retardation Protein (FMRP), a RNA binding protein involved in multiple steps of RNA metabolism, and modulating the translation of thousands of proteins including a large set of synaptic proteins. Despite differences in genetic etiology, there are overlapping features in RTT and FXS, possibly due to interactions between MeCP2 and FMRP, and to the regulation of pathways resulting in dysregulation of common molecular signaling. Furthermore, basic physiological mechanisms are regulated by these proteins and might concur to the pathophysiology of both syndromes. Considering that RTT and FXS are disorders affecting brain development, and that most of the common targets of MeCP2 and FMRP are involved in brain activity, we discuss the mechanisms of synaptic function and plasticity altered in RTT and FXS, and we consider the similarities and the differences between these two disorders.

Keywords: FMRP; Fragile X syndrome; MeCP2; Rett syndrome; neurodevelopmental disorders; synaptic plasticity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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References

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[1] Abdala A. P., Toward M. A., Dutschmann M., Bissonnette J. M., Paton J. F. R. (2016). Deficiency of GABAergic synaptic inhibition in the Kolliker-Fuse area underlies respiratory dysrhythmia in a mouse model of Rett syndrome. J. Physiol. 594 223–237. 10.1113/JP270966 - DOI - PMC - PubMed

[2] Abdala A. P., Toward M. A., Dutschmann M., Bissonnette J. M., Paton J. F. R. (2016). Deficiency of GABAergic synaptic inhibition in the Kolliker-Fuse area underlies respiratory dysrhythmia in a mouse model of Rett syndrome. J. Physiol. 594 223–237. 10.1113/JP270966 - DOI - PMC - PubMed

[3] Abuhatzira L., Makedonski K., Kaufman Y., Razin A., Shemer R. (2007). MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production. Epigenetics 2 214–222. 10.4161/epi.2.4.5212 - DOI - PubMed

[4] Abuhatzira L., Makedonski K., Kaufman Y., Razin A., Shemer R. (2007). MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production. Epigenetics 2 214–222. 10.4161/epi.2.4.5212 - DOI - PubMed

[5] Amir R. E., Van Den Veyver I. B., Wan M., Tran C. Q., Francke U., Zoghbi H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat. Genet. 23 185–188. 10.1038/13810 - DOI - PubMed

[6] Amir R. E., Van Den Veyver I. B., Wan M., Tran C. Q., Francke U., Zoghbi H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat. Genet. 23 185–188. 10.1038/13810 - DOI - PubMed

[7] Anastasia A., Deinhardt K., Chao M. V., Will N. E., Irmady K., Lee F. S., et al. (2013). Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat. Commun. 4:2490. 10.1038/ncomms3490 - DOI - PMC - PubMed

[8] Anastasia A., Deinhardt K., Chao M. V., Will N. E., Irmady K., Lee F. S., et al. (2013). Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat. Commun. 4:2490. 10.1038/ncomms3490 - DOI - PMC - PubMed

[9] Arbab T., Battaglia F. P., Pennartz C. M. A., Bosman C. A. (2018). Abnormal hippocampal theta and gamma hypersynchrony produces network and spike timing disturbances in the Fmr1-KO mouse model of Fragile X syndrome. Neurobiol. Dis. 114 65–73. 10.1016/j.nbd.2018.02.011 - DOI - PubMed

[10] Arbab T., Battaglia F. P., Pennartz C. M. A., Bosman C. A. (2018). Abnormal hippocampal theta and gamma hypersynchrony produces network and spike timing disturbances in the Fmr1-KO mouse model of Fragile X syndrome. Neurobiol. Dis. 114 65–73. 10.1016/j.nbd.2018.02.011 - DOI - PubMed

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Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Affiliations

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Authors

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Abstract

Conflict of interest statement

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Abstract

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