Novel frameshift mutations of ANKUB1, GLI3, and TAS2R3 associated with polysyndactyly in a Chinese family

Zhang, Lishan; Chen, Xiaobin; Xu, Lanwei; Guan, Sheng; Wu, De‐Hua; Lin, Yen‐Ting; Wang, Zengtao

doi:10.1002/mgg3.1223

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…Another study suggested that point mutation in CNKSR2 is associated with seizures and mild intellectual disability (8). In 2020 a report was published hypothesizing that frameshift mutations of GLI3, ANKUB1, and TAS2R3 might alter the functions of proteins, and accelerate the progression of Polysyndactyly (PSD); an autosomal dominant genetic limb malformation (10). It has been proposed that the EP400 gene plays a significant role in oligodendrocyte survival and myelination in the vertebrate central nervous system (11).…”

Section: Discussionmentioning

confidence: 99%

Computational and experimental hunt for expansion prone tandem CNG repeats in human genomes

Suroliya

Uppili

Kumar

et al. 2023

Preprint

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Introduction: Spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders. Tandem repeat expansion is the pathogenic mutation in most of SCA cases. The pathophysiology of SCAs is still not completely defined due to the lack of genetic mutation in around 50% of cases worldwide. These uncharacterized cases must be genetically diagnosed for a better understanding and future treatment purposes. In this study, we tried a combination of computational and experimental approaches to find out novel CNG repeat loci that may be associated with SCAs. Methodology: We investigate the human reference genome (hg-37) to find out all the possible CNG repeats present in more than 3 continuous uninterrupted units and annotated their functional locations. For experiment purposes, we targeted 52 loci from exonic and UTR regions and screened them in our 100 control samples through fragment analysis to know their polymorphic status. All the highly polymorphic loci were further investigated in 100 patient samples to know any large repeat expansion. Results: There are 15069 CNG repeat loci present in the human genome. After the examination of 52 loci in the control samples, 19 loci showed a highly polymorphic repeat pattern and were screened in patients. The 1000 genome different population data also suggested the polymorphic status in the available 15 loci data. From the GTEx database, 18 loci proposed the expression in the brain, suggesting any variation in these genes may cause neurological disorders. Conclusion: We tried a different kind of approach to find out tandem repeat expansion mutation in a cost-effective manner. Although we were unable to identify any disease-causing mutation in our patient cohort recently, various studies from different populations of the world have vouched for the genetic changes in these genes like GLS, RAI1, GIPC1, and CNKSR2 resulted in neurological disorders. Moreover, publications on the same identified repeats in GIPC1 for OPMD and GLS for ataxia with developmental delay, confirm the hypothesis to evaluate these repeat loci in different populations and other neurological disorders to identify novel targets.

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Section: Discussionmentioning

confidence: 99%

Computational and experimental hunt for expansion prone tandem CNG repeats in human genomes

Suroliya

Uppili

Kumar

et al. 2023

Preprint

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“…This PP2A‐dependent regulatory domain was mapped on the GLI3 protein in between amino acid 568 and 1100 (Krauß et al, 2009). To date, more than 223 GLI3 pathogenic variants have been identified in several human genetic diseases (L. Zhang et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Novel GLI3 pathogenic variants in complex pre‐ and postaxial polysyndactyly and Greig cephalopolysyndactyly syndrome

Patel

Singh²,

Ali

2020

American J of Med Genetics Pt A

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Polydactyly is a limb malformation and can occur as nonsyndromic polydactyly, syndromic polydactyly, or along with other limb defects. A few genes have been identified that cause various forms of syndromic and nonsyndromic polydactyly, of which GLI3 has been extensively explored. In the present study, GLI3 gene was screened by direct resequencing in 15 polydactyly cases with or without other anomalies. GLI3 screening revealed two novel pathogenic variants, NM_000168.6:c.3414delC [p.(H1138Qfs*68)] and NM_000168.6:c.1862C>T [p.(P621L)], found in two unrelated cases of familial complex pre‐ and postaxial polysyndactyly and sporadic Greig cephalopolysyndactyly syndrome (GCPS), respectively. The first pathogenic GLI3 variant, NM_000168.6:c.3414delC, causes premature protein truncation at the C‐terminal domain of GLI3. Alternatively, the second pathogenic variant, NM_000168.6:c.1862C>T, lies in the DNA binding domain of GLI3 protein and may affect its hydrophobic interaction with DNA. Both pathogenic GLI3 variants had reduced transcriptional activity in HEK293 cells that likely had led to haploinsufficiency and, consequently, the clinical phenotypes. Overall, the present study reports a novel familial case of complex pre‐ and postaxial polysyndactyly and the underlying novel pathogenic GLI3 variant expanding the clinical criteria for GLI3 mutational spectrum to complex pre‐ and postaxial polysyndactyly. Furthermore, this study also reports a novel GLI3 pathogenic variant linked to GCPS, highlighting the known genotype–phenotype correlation.

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Identifying unstable CNG repeat loci in the human genome: a heuristic approach and implications for neurological disorders

Suroliya,

Uppili,

Kumar

et al. 2024

Hum Genome Var

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Tandem nucleotide repeat (TNR) expansions, particularly the CNG nucleotide configuration, are associated with a variety of neurodegenerative disorders. In this study, we aimed to identify novel unstable CNG repeat loci associated with the neurogenetic disorder spinocerebellar ataxia (SCA). Using a computational approach, 15,069 CNG repeat loci in the coding and noncoding regions of the human genome were identified. Based on the feature selection criteria (repeat length >10 and functional location of repeats), we selected 52 repeats for further analysis and evaluated the repeat length variability in 100 control subjects. A subset of 19 CNG loci observed to be highly variable in control subjects was selected for subsequent analysis in 100 individuals with SCA. The genes with these highly variable repeats also exhibited higher gene expression levels in the brain according to the tissue expression dataset (GTEx). No pathogenic expansion events were identified in patient samples, which is a limitation given the size of the patient group examined; however, these loci contain potential risk alleles for expandability. Recent studies have implicated GLS, RAI1, GIPC1, MED15, EP400, MEF2A, and CNKSR2 in neurological diseases, with GLS, GIPC1, MED15, RAI1, and MEF2A sharing the same repeat loci reported in this study. This finding validates the approach of evaluating repeat loci in different populations and their possible implications for human pathologies.

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Novel frameshift mutations of ANKUB1, GLI3, and TAS2R3 associated with polysyndactyly in a Chinese family

Cited by 3 publications

References 24 publications

Computational and experimental hunt for expansion prone tandem CNG repeats in human genomes

Computational and experimental hunt for expansion prone tandem CNG repeats in human genomes

Novel GLI3 pathogenic variants in complex pre‐ and postaxial polysyndactyly and Greig cephalopolysyndactyly syndrome

Identifying unstable CNG repeat loci in the human genome: a heuristic approach and implications for neurological disorders

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