Mechanisms of Genome Instability in the Fragile X-Related Disorders

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2021 Oct 23

PMID 34681027

Citations 5

Authors

Bruce E Hayward

Karen Usdin

Affiliations

Soon will be listed here.

Abstract

The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5' UTR of the X-linked gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological allele size classes are distinguished. Premutation (PM) alleles have 54-200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes.

Citing Articles

Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model.

Kojak N, Kuno J, Fittipaldi K, Khan A, Wenger D, Glasser M Nucleic Acids Res. 2024; 52(10):5732-5755.

PMID: 38597682 PMC: 11162798. DOI: 10.1093/nar/gkae250.

Editorial for the Fragile X Syndrome Genetics Special Issue: May 2023.

Godler D, Brown W Genes (Basel). 2023; 14(6).

PMID: 37372328 PMC: 10297929. DOI: 10.3390/genes14061148.

Dynamic alternative DNA structures in biology and disease.

Wang G, Vasquez K Nat Rev Genet. 2022; 24(4):211-234.

PMID: 36316397 PMC: 11634456. DOI: 10.1038/s41576-022-00539-9.

Fragile X Syndrome Caused by Maternal Somatic Mosaicism of Gene: Case Report and Literature Review.

Gomez-Rodriguez M, Morales-Conejo M, Arteche-Lopez A, Sanchez-Calvin M, Quesada-Espinosa J, Gomez-Manjon I Genes (Basel). 2022; 13(9).

PMID: 36140775 PMC: 9498456. DOI: 10.3390/genes13091609.

Searching for New Z-DNA/Z-RNA Binding Proteins Based on Structural Similarity to Experimentally Validated Zα Domain.

Bartas M, Slychko K, Brazda V, cerven J, Beaudoin C, Blundell T Int J Mol Sci. 2022; 23(2).

PMID: 35054954 PMC: 8775963. DOI: 10.3390/ijms23020768.

References

Abu Diab M, Mor-Shaked H, Cohen E, Cohen-Hadad Y, Ram O, Epsztejn-Litman S . The G-rich Repeats in and Loci Are Hotspots for Local Unpairing of DNA. Genetics. 2018; 210(4):1239-1252. PMC: 6283162. DOI: 10.1534/genetics.118.301672. View

Gerhardt J, Tomishima M, Zaninovic N, Colak D, Yan Z, Zhan Q . The DNA replication program is altered at the FMR1 locus in fragile X embryonic stem cells. Mol Cell. 2013; 53(1):19-31. PMC: 3920742. DOI: 10.1016/j.molcel.2013.10.029. View

Garribba L, Bjerregaard V, Goncalves Dinis M, Ozer O, Wu W, Sakellariou D . Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells. Proc Natl Acad Sci U S A. 2020; 117(28):16527-16536. PMC: 7368274. DOI: 10.1073/pnas.1921219117. View

Fojtik P, Vorlickova M . The fragile X chromosome (GCC) repeat folds into a DNA tetraplex at neutral pH. Nucleic Acids Res. 2001; 29(22):4684-90. PMC: 92515. DOI: 10.1093/nar/29.22.4684. View

Wohrle D, Salat U, Hameister H, Vogel W, Steinbach P . Demethylation, reactivation, and destabilization of human fragile X full-mutation alleles in mouse embryocarcinoma cells. Am J Hum Genet. 2001; 69(3):504-15. PMC: 1235481. DOI: 10.1086/322739. View

Mollersen L, Rowe A, Larsen E, Rognes T, Klungland A . Continuous and periodic expansion of CAG repeats in Huntington's disease R6/1 mice. PLoS Genet. 2010; 6(12):e1001242. PMC: 3000365. DOI: 10.1371/journal.pgen.1001242. View

Glaser D, Wohrle D, Salat U, Vogel W, Steinbach P . Mitotic behavior of expanded CGG repeats studied on cultured cells: further evidence for methylation-mediated triplet repeat stability in fragile X syndrome. Am J Med Genet. 1999; 84(3):226-8. View

Zhao X, Gazy I, Hayward B, Pintado E, Hwang Y, Tassone F . Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model. Brain Sci. 2019; 9(3). PMC: 6468611. DOI: 10.3390/brainsci9030052. View

Paulson H . Repeat expansion diseases. Handb Clin Neurol. 2018; 147:105-123. PMC: 6485936. DOI: 10.1016/B978-0-444-63233-3.00009-9. View

10.

Zhao X, Usdin K . Timing of Expansion of Fragile X Premutation Alleles During Intergenerational Transmission in a Mouse Model of the Fragile X-Related Disorders. Front Genet. 2018; 9:314. PMC: 6096447. DOI: 10.3389/fgene.2018.00314. View

11.

Gronskov K, Hjalgrim H, Bjerager M, Brondum-Nielsen K . Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression. Am J Hum Genet. 1997; 61(4):961-7. PMC: 1716002. DOI: 10.1086/514872. View

12.

Grasso M, Faravelli F, Lo Nigro C, Chiurazzi P, Sperandeo M, Argusti A . Mosaicism for the full mutation and a microdeletion involving the CGG repeat and flanking sequences in the FMR1 gene in eight fragile X patients. Am J Med Genet. 1999; 85(3):311-6. DOI: 10.1002/(sici)1096-8628(19990730)85:3<311::aid-ajmg24>3.0.co;2-a. View

13.

Orrico A, Galli L, Dotti M, Plewnia K, Censini S, Federico A . Mosaicism for full mutation and normal-sized allele of the FMR1 gene: a new case. Am J Med Genet. 1998; 78(4):341-4. View

14.

Zhao X, Kumari D, Gupta S, Wu D, Evanitsky M, Yang W . Mutsβ generates both expansions and contractions in a mouse model of the Fragile X-associated disorders. Hum Mol Genet. 2015; 24(24):7087-96. PMC: 4654059. DOI: 10.1093/hmg/ddv408. View

15.

Brown R, Freudenreich C . Structure-forming repeats and their impact on genome stability. Curr Opin Genet Dev. 2020; 67:41-51. PMC: 8084909. DOI: 10.1016/j.gde.2020.10.006. View

16.

Yrigollen C, Martorell L, Durbin-Johnson B, Naudo M, Genoves J, Murgia A . AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission. J Neurodev Disord. 2014; 6(1):24. PMC: 4126815. DOI: 10.1186/1866-1955-6-24. View

17.

Martin J, Bell J . A PEDIGREE OF MENTAL DEFECT SHOWING SEX-LINKAGE. J Neurol Psychiatry. 2011; 6(3-4):154-7. PMC: 1090429. DOI: 10.1136/jnnp.6.3-4.154. View

18.

Zhao X, Lokanga R, Allette K, Gazy I, Wu D, Usdin K . A MutSβ-Dependent Contribution of MutSα to Repeat Expansions in Fragile X Premutation Mice?. PLoS Genet. 2016; 12(7):e1006190. PMC: 4948851. DOI: 10.1371/journal.pgen.1006190. View

19.

Suelves N, Kirkham-McCarthy L, Lahue R, Gines S . A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease mice. Sci Rep. 2017; 7(1):6082. PMC: 5519595. DOI: 10.1038/s41598-017-05125-2. View

20.

Khristich A, Mirkin S . On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability. J Biol Chem. 2020; 295(13):4134-4170. PMC: 7105313. DOI: 10.1074/jbc.REV119.007678. View