Mechanisms of Genome Instability in the Fragile X-Related Disorders

Hayward, Bruce E.; Usdin, Karen

doi:10.3390/genes12101633

Cited by 7 publications

(3 citation statements)

References 105 publications

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“…Mosaicisms in FXS usually refer to two different FMR1 alterations, size and methylation mosaicisms [ 8 ]. The most common is “size mosaicism”, detected in 38% of the patients, which results in a variable clinical phenotype depending on the proportion of cells that have normal premutation alleles (55–200 CGGs) or FM alleles [ 9 ]. In addition, there are numerous cases of “methylation mosaicism”, in which an FM allele is fully or partially methylated.…”

Section: Discussionmentioning

confidence: 99%

Fragile X Syndrome Caused by Maternal Somatic Mosaicism of FMR1 Gene: Case Report and Literature Review

Gómez-Rodriguez

Morales-Conejo

Arteche‐López

et al. 2022

Genes

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Fragile X syndrome (FXS) is caused by an abnormal expansion of the number of trinucleotide CGG repeats located in the 5′ UTR in the first exon of the FMR1 gene. Size and methylation mosaicisms are commonly observed in FXS patients. Both types of mosaicisms might be associated with less severe phenotypes depending on the number of cells expressing FMRP. Although this dynamic mutation is the main underlying cause of FXS, other mechanisms, including point mutations or deletions, can lead to FXS. Several reports have demonstrated that de novo deletions including the entire or a portion of the FMR1 gene end up with the absence of FMRP and, thus, can lead to the typical clinical features of FXS. However, very little is known about the clinical manifestations associated with FMR1 gene deletions in mosaicism. Here, we report an FXS case caused by an entire hemizygous deletion of the FMR1 gene caused by maternal mosaicism. This manuscript reports this case and a literature review of the clinical manifestations presented by carriers of FMR1 gene deletions in mosaicism.

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Section: Discussionmentioning

confidence: 99%

Fragile X Syndrome Caused by Maternal Somatic Mosaicism of FMR1 Gene: Case Report and Literature Review

Gómez-Rodriguez

Morales-Conejo

Arteche‐López

et al. 2022

Genes

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“…Local DNA structures, also called ‘non-B’ DNA structures, have been recognised as important regulators of many fundamental regulatory processes, including replication [ 1 ], transcription [ 2 ], translation [ 3 ], epigenetics [ 4 ], DNA damage repair [ 5 , 6 , 7 ], genome evolution and rearrangement [ 8 ]. Negative supercoiling of DNA and protein binding can increase the stability of local DNA conformation and/or induce conformational changes that give rise to various alternative DNA structures, the best-described being cruciforms [ 7 ], Z-DNA/Z-RNA [ 9 , 10 ], triplexes [ 11 ] and quadruplexes [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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

Bartas

Slychko

Brázda

et al. 2022

IJMS

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Z-DNA and Z-RNA are functionally important left-handed structures of nucleic acids, which play a significant role in several molecular and biological processes including DNA replication, gene expression regulation and viral nucleic acid sensing. Most proteins that have been proven to interact with Z-DNA/Z-RNA contain the so-called Zα domain, which is structurally well conserved. To date, only eight proteins with Zα domain have been described within a few organisms (including human, mouse, Danio rerio, Trypanosoma brucei and some viruses). Therefore, this paper aimed to search for new Z-DNA/Z-RNA binding proteins in the complete PDB structures database and from the AlphaFold2 protein models. A structure-based similarity search found 14 proteins with highly similar Zα domain structure in experimentally-defined proteins and 185 proteins with a putative Zα domain using the AlphaFold2 models. Structure-based alignment and molecular docking confirmed high functional conservation of amino acids involved in Z-DNA/Z-RNA, suggesting that Z-DNA/Z-RNA recognition may play an important role in a variety of cellular processes.

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“…For the molecular component, Hayward and Usdin [ 5 ] review the current state of knowledge on the mechanisms of somatic and germline instability of expanded FMR1 alleles in Fragile X-related disorders. The review discusses the potential impact of mosaicism for FMR1 alleles of different CGG expansion sizes, on clinical presentation.…”

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confidence: 99%