Deletion of a non-canonical regulatory sequence causes loss of <i>Scn1a</i> expression and epileptic phenotypes in mice

Haigh, Jessica L; Adhikari, Anna; Copping, Nycole A; Stradleigh, Tyler W.; Wade, A. Ayanna; Catta-Preta, Rinaldo; Su-Feher, Linda; Zdilar, Iva; Morse, Sarah; Fenton, Timothy A.; Nguyen, Anh B; Quintero, Diana; Sramek, Michael; Carter, Jasmine L; Gompers, Andrea; Lambert, Jason T.; Canales, Cesar P; Pennacchio, Len A.; Visel, Axel; Dickel, Diane E.; Silverman, Jill L.; Nord, A.

doi:10.1101/766634

Cited by 5 publications

(9 citation statements)

References 87 publications

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“…Spectral analysis was performed in Python using MEG and EEG analysis and visualization (MNE) open-source software, as previously described in ( 59 , 61 ). Frequency bands were defined as delta 0.5–4 Hz, theta 5–9 Hz, alpha 9–12 Hz, beta 13–30 Hz and gamma 30–50 Hz.…”

Section: Methodsmentioning

confidence: 99%

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Adhikari

Copping

Beegle

et al. 2021

Human Molecular Genetics

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Angelman Syndrome is a rare neurodevelopmental disorder characterized by impaired communication skills, ataxia, motor and balance deficits, intellectual disabilities, and seizures. The genetic cause of Angelman syndrome is the neuronal loss of UBE3A expression in the brain. A novel approach, described here, is a stem cell gene therapy which uses lentivector transduced hematopoietic stem and progenitor cells to deliver functional UBE3A to affected cells. We have demonstrated both the prevention and reversal of Angelman syndrome phenotypes upon transplantation and engraftment of human CD34+ cells transduced with a Ube3a lentivector in a novel immunodeficient Ube3amat−/pat+ IL2rg−/y mouse model of Angelman syndrome. A significant improvement in motor and cognitive behavioral assays as well as normalized delta power measured by EEG was observed in neonates and adults transplanted with the gene modified cells. Human hematopoietic profiles observed in the lymphoid organs by detection of human immune cells were normal. Expression of UBE3A was detected in the brains of the adult treatment group following immunohistochemical staining illustrating engraftment of the gene modified cells expressing UBE3A in the brain. As demonstrated with our data, this stem cell gene therapy approach offers a promising treatment strategy for Angelman syndrome, not requiring a critical treatment window.

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Section: Methodsmentioning

confidence: 99%

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Adhikari

Copping

Beegle

et al. 2021

Human Molecular Genetics

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“…Nakayama et al described two cases of Dravet syndrome carrying microdeletions in the SCN1A promoter region that resulted in SCN1A haploinsufficiency and reduced channel protein levels, leading to Dravet Syndrome [143]. Additionally, Haigh and colleagues have shown that mice harbouring deletions in the non‐canonical promoter region of Scn1a , which include the alternative TSS 1b, exhibit a significant reduction in the expression of Scn1a and an epileptic phenotype [144, 145].…”

Section: Evidence Of Non‐coding Variation In the Epilepsiesmentioning

confidence: 99%

Non‐coding regulatory elements: Potential roles in disease and the case of epilepsy

Pagni

Frankish

Mudge

et al. 2021

Neuropathology Appl Neurobio

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Non‐coding DNA (ncDNA) refers to the portion of the genome that does not code for proteins and accounts for the greatest physical proportion of the human genome. ncDNA includes sequences that are transcribed into RNA molecules, such as ribosomal RNAs (rRNAs), microRNAs (miRNAs), long non‐coding RNAs (lncRNAs) and un‐transcribed sequences that have regulatory functions, including gene promoters and enhancers. Variation in non‐coding regions of the genome have an established role in human disease, with growing evidence from many areas, including several cancers, Parkinson's disease and autism. Here, we review the features and functions of the regulatory elements that are present in the non‐coding genome and the role that these regions have in human disease. We then review the existing research in epilepsy and emphasise the potential value of further exploring non‐coding regulatory elements in epilepsy. In addition, we outline the most widely used techniques for recognising regulatory elements throughout the genome, current methodologies for investigating variation and the main challenges associated with research in the field of non‐coding DNA.

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“…Transcriptomic datasets generated for this study are available via the Gene Expression Omnibus (GEO) archive under accessions GSE169481 www.ncbi. nlm.nih.gov/bioproject/PRJNA716688 [97] and GSE169485 www.ncbi.nlm.nih. gov/bioproject/PRJNA716683 [98].…”

Section: Supplementary Informationmentioning

confidence: 99%

“…nlm.nih.gov/bioproject/PRJNA716688 [97] and GSE169485 www.ncbi.nlm.nih. gov/bioproject/PRJNA716683 [98]. Differential Hi-C comparisons used GEO accession GSE87112, www.ncbi.nlm.nih.gov/bioproject/PRJNA343608 [39].…”

Section: Supplementary Informationmentioning

confidence: 99%

Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice

et al. 2021

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Background Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency; however, putative causal non-coding promoter mutations have been identified. Methods To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We generated a transgenic mouse line with deletion of the extended evolutionarily conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alterations in behavior. Results Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and behavioral deficits. Conclusions This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A. We identified the 1b region as a critical disease-relevant regulatory element and provide evidence that non-canonical and seemingly redundant promoters can have essential function.

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Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice

Cited by 5 publications

References 87 publications

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells

Non‐coding regulatory elements: Potential roles in disease and the case of epilepsy

Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice

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