Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements

Primary distal renal tubular acidosis (dRTA) is a rare tubular disease associated with variants in SLC4A1, ATP6V0A4, ATP6V1B1, FOXⅠ1 or WDR72 genes. Currently, there is growing evidence that all types of exonic variants can alter splicing regulatory elements, affecting the pre-mRNA splicing process. This study was to determine the consequences of variants associated with dRTA on pre-mRNA splicing combined with predictive bioinformatics tools and minigene assay. As a result, among the 15 candidate variants, 8 variants distributed in SLC4A1 (c.1765C>T, p.Arg589Cys), ATP6V1B1( c.368G>T, p.Gly123Val; c.370C>T, p.Arg124Trp; c.484G>T, p.Glu162* and c.1102G>A, p.Glu368Lys) and ATP6V0A4 genes (c.322C>T, p.Gln108*; c.1571C>T, p.Pro524Leu and c.1572G>A, p.Pro524Pro) were identified to result in whole or part of exon skipping by either disruption of ESEs and generation of ESSs, or interference with the recognition of the classic splicing site, or both. To our knowledge, this is the first study on pre-mRNA splicing of exonic variants in the dRTA-related genes. These results highlight the importance of assessing the effects of exonic variants at the mRNA level and suggest that minigene analysis is an effective tool for evaluating the effects of splicing on variants in vitro

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TAU GENE MUTATIONS IN FRONTOTEMPORAL DEMENTIA AND PARKINSONISM LINKED TO CHROMOSOME 17

Society and Structures ◽

10.1142/9789812705150_0071 ◽

2003 ◽

Author(s):

MARIA GRAZIA SPILLANTINI

Keyword(s):

Frontotemporal Dementia ◽

Gene Mutations ◽

Chromosome 17

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Disruption of splicing-regulatory elements using CRISPR/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice

National Science Review ◽

10.1093/nsr/nwz131 ◽

2019 ◽

Vol 7 (1) ◽

pp. 92-101 ◽

Cited By ~ 2

Author(s):

Jin-Jing Li ◽

Xiang Lin ◽

Cheng Tang ◽

Ying-Qian Lu ◽

Xinde Hu ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Rna Splicing ◽

Muscular Atrophy ◽

Regulatory Elements ◽

Survival Motor Neuron ◽

A Genome ◽

Human Ipscs ◽

New Strategy ◽

Splicing Regulatory Elements

Abstract We here report a genome-editing strategy to correct spinal muscular atrophy (SMA). Rather than directly targeting the pathogenic exonic mutations, our strategy employed Cas9 and guide-sgRNA for the targeted disruption of intronic splicing-regulatory elements. We disrupted intronic splicing silencers (ISSs, including ISS-N1 and ISS + 100) of survival motor neuron (SMN) 2, a key modifier gene of SMA, to enhance exon 7 inclusion and full-length SMN expression in SMA iPSCs. Survival of splicing-corrected iPSC-derived motor neurons was rescued with SMN restoration. Furthermore, co-injection of Cas9 mRNA from Streptococcus pyogenes (SpCas9) or Cas9 from Staphylococcus aureus (SaCas9) alongside their corresponding sgRNAs targeting ISS-N1 into zygotes rescued 56% and 100% of severe SMA transgenic mice (Smn−/−, SMN2tg/−). The median survival of the resulting mice was extended to >400 days. Collectively, our study provides proof-of-principle for a new strategy to therapeutically intervene in SMA and other RNA-splicing-related diseases.

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Tau Gene Mutations in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 (FTDP-17): Their Relevance for Understanding the Neurogenerative Process

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2000.tb06907.x ◽

2006 ◽

Vol 920 (1) ◽

pp. 74-83 ◽

Cited By ~ 36

Author(s):

MICHEL GOEDERT ◽

BERNARDINO GHETTI ◽

MARIA GRAZIA SPILLANTINI

Keyword(s):

Frontotemporal Dementia ◽

Gene Mutations ◽

Chromosome 17

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A Comprehensive Analysis and Splicing Characterization of Naturally Occurring Synonymous Variants in the ATP7B Gene

Frontiers in Genetics ◽

10.3389/fgene.2020.592611 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaoying Zhou ◽

Wei Zhou ◽

Chunli Wang ◽

Lan Wang ◽

Yu Jin ◽

...

Keyword(s):

Rna Splicing ◽

Genetic Diseases ◽

Genetic Diagnosis ◽

Exon Skipping ◽

Computational Prediction ◽

Regulatory Elements ◽

Naturally Occurring ◽

Splicing Regulatory Elements ◽

The Impact

Next-generation sequencing is effective for the molecular diagnosis of genetic diseases. However, the identification of the clinical significance of synonymous variants remains a challenge. Our previous study showed that some synonymous variants in ATP7B gene produced splicing disruptions, leading to Wilson disease (WD). To test the hypothesis that synonymous variants of ATP7B cause abnormal splicing by disrupting authentic splice sites or splicing regulatory elements, we used computational tools and minigene assays to characterize 253 naturally occurring ATP7B gene synonymous variants in this study. Human Splicing Finder (HSF) and ESE Finder 3.0 were used to predict the impact of these rare synonymous variants on pre-mRNA splicing. Then, we cloned 14 different wild-type Minigene_ATP7B_ex constructs for in vitro minigene assay, including 16 exons of ATP7B gene. After computational prediction, 85 candidate variants were selected to be introduced into the corresponding Minigene_ATP7B_ex constructs for splicing assays. Using this two-step procedure, we demonstrated that 11 synonymous variants in ExAc database (c.1620C>T, c.3888C>T, c.1554C>T, c.1677C>T, c.1830G>A, c.1875T>A, c.2826C>A, c.4098G>A, c.2994C>T, c.3243G>A, and c.3747G>A) disrupted RNA splicing in vitro, and two (c.1620C>T and c.3243G>A) of these caused a complete exon skipping. The results not only provided a reliable experimental basis for the genetic diagnosis of WD patients but also offered some new insights into the pathogenicity of synonymous variants in genetic diseases.

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