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Biological and genetic factors in DCD
Published in Anna L. Barnett, Elisabeth L. Hill, Understanding Motor Behaviour in Developmental Coordination Disorder, 2019
Melissa K. Licari, Daniela Rigoli, Jan P. Piek
A recent study by Mosca et al. (2016) was the first to specifically concentrate on the genetic origins of DCD. The study examined copy number variations (CNVs) and structural variation of base pairs within DNA in 82 children with DCD, with and without co-occurring ADHD and reading disorder. The study found greater genomic variation, with 26% of the DCD cohort displaying rare de novo CNVs, and 64% inherited CNVs from a parent who also had a neurodevelopmental disorder. The study also found an enrichment of duplications for brain expressed genes, along with an overlap in duplications and deletions in genes previously implicated in other neurological and neurodevelopmental disorders, including FHIT, GAP43, RBFOX1, PTPRN2, SHANK3, 16p11.2 and 22q11.2 seen in ADHD, ASD, epilepsy, schizophrenia and Tourette’s syndrome. While a number of the variations were seen in children with co-occurring disorders, there was also presence of variations in children with isolated cases of DCD, providing significant evidence to support that this disorder has a genetic basis that is heritable.
Choroid Plexus Tumors
Published in Dongyou Liu, Tumors and Cancers, 2017
Specific gene alterations in CPP include ARL4A (7p21.3) and those encoding Notch receptors (Notch 1, 2, and 3). Specific gene mutations involved in CPC include RAB6B, C3orf36, SLCO2A1, and RYK (3q22); POLH, GTPBP2, MAD2L1BP, MRPS18A, RSPH9, and VEGFA (6p21); RBFOX1 (16p13.3); and PDGF. Several oncogenes (e.g., Taf12, Nfyc, and Rad54l) have also been implicated in the initiation and maintenance of CPC, as overexpression of these genes accelerates CPC tumorigenesis in cooperation with deletion of Trp53, Rb, and Pten [2].
Novel approaches to targeted protein degradation technologies in drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Yu Xue, Andrew A. Bolinger, Jia Zhou
It is worth noting that some new types of PROTACs, such as peptide-based PROTACs and nucleotide-based PROTACs are also emerging rapidly. Peptide-based PROTACs consist of protein-binding domain (PBD), proteasome targeting motif (PTM), and a cell penetrating moiety (CPD). Based on this guideline, Zhang’s group reported a cell-permeable peptide-based PROTAC to degrade α-synuclein, which may have potential for the treatment of Parkinson’s disease (PD) [73]. In addition, peptide-based PROTACs with α-helical structure to gain better proteolytic stability, cellular permeability, and PK profiles have also been reported [74,75]. Developing nucleotide-based PROTACs represents another innovative approach to address the degradation of TFs and RNA-binding proteins (RBPs) through the binding of oligonucleotide to target proteins. Hall’s group first reported a single-strand RNA-PROTAC to degrade two RBPs, Lin28A (a stem cell factor) and RBFOX1 (a splicing factor) in two cancer cell lines via VHL-mediated pathway [76]. Further efforts have expanded the POI ligand to double-strand nucleotides [77,78] and nucleic acid aptamers [79]. Collectively, while the aforementioned PROTAC approaches cannot fully describe the current status of PROTAC development, these endeavors suggest a way forward for PROTAC to develop technology to make such molecules more widely applicable, more efficient, less toxic, and easier to deliver.
Advances in the discovery of microRNA-based anticancer therapeutics: latest tools and developments
Published in Expert Opinion on Drug Discovery, 2020
Kenneth K.W. To, Winnie Fong, Christy W.S. Tong, Mingxia Wu, Wei Yan, William C.S. Cho
miRNA and RBPs are two major players regulating mRNA stability and translation in eukaryotic cells. While miRNA and RBP may interact with the same 3ʹ-untranslated region of their target mRNAs to mediate the regulation, they may act in concert or exhibit opposing regulatory effects. Interestingly, miRNA and RBP may also regulate the translation and activity of each other [85]. In recent years, the complex interplay between miRNA and RBP and its relevance to cancer development and progression have attracted a lot of attention. Chen et al. reported the use of recombinant RBPs to suppress miR-21 expression in cancer cells to elicit anticancer effect [86]. Mutations were introduced into the RNA recognition motif (RRM) of the human RBP Rbfox1, which allowed it to specifically recognize the UGAAUC motif in the terminal loop of pre-miR-21 and effectively suppress miR-21 levels to reduce cell viability in HeLa cells [86]. However, this approach may not be directly exploited for other RBP–miRNA interaction because the typical affinity of a single RRM domain is only in the micromolar range and a single RRM may not be sufficient for specific interaction with miRNA. To this end, other engineered RBPs (including the Pumuluo and FBF homolog (PUF) and the pentatricopeptide repeat (PPR) proteins) have been investigated to target specific miRNAs [87], which may be further developed as a novel means to treat cancer.
Microexons: novel regulators of the transcriptome
Published in Journal of Human Transcriptome, 2018
Ashton Curry-Hyde, Bei Jun Chen, James D. Mills, Michael Janitz
ASD has been linked to neural-specific AS misregulation in microexons [21], specifically RBFox1-dependent AS [5]. Almost 30% of AS microexons in the brains of individuals with ASD were misregulated, a percentage that is directly correlated to the level of nSR100 expression levels in the same patients [21,23]. Extensive AS pattern deviation in cortical regions of the brain in ASD is related to splicing misregulation in ASD genes (e.g. neurixin and neuroligins), in addition to evidence shown by transcriptomic profiling in cases of ASD [25]. The study found an association between the reduction in the level of the neuronal-specific splicing factor nSR100, which regulates neural microexons by binding to ISE motifs, and microexon misregulation in the brains of people with ASD.