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Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.

ABSTRACT: Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors.

SUBMITTER: Martins Custodio H

PROVIDER: S-EPMC10473570 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.

Martins Custodio Helena H Clayton Lisa M LM Bellampalli Ravishankara R Pagni Susanna S Silvennoinen Katri K Caswell Richard R Brunklaus Andreas A Guerrini Renzo R Koeleman Bobby P C BPC Lemke Johannes R JR Møller Rikke S RS Scheffer Ingrid E IE Weckhuysen Sarah S Zara Federico F Zuberi Sameer S Kuchenbaecker Karoline K Balestrini Simona S Mills James D JD Sisodiya Sanjay M SM

Brain : a journal of neurology 20230901 9

Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as ...[more]

PMID: 37006128

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Project description:Assessment of non-target impacts of pesticides used widely in agriculture and pest management rarely considers reptiles. Despite their integral role in all ecosystems, particularly arid ecosystems, reptiles are not included in risk assessments. Two pesticides used in agricultural pest management are fipronil and fenitrothion. Here, we used a field-based BACI design experiment in semi-arid Australia to investigate the impact of these pesticides on basic physiological and behavioural parameters of a common arid-zone lizard species, Pogona vitticeps. Fipronil and fenitrothion were applied at ecologically relevant doses via oral gavage. Before and after dosing, blood, physical activity and body condition parameters were assessed. We found that temperature significantly influenced lizard activity in the morning period of movement; however, fipronil-treated individuals moved at least 49% less than fenitrothion-treated and control lizards from 7 days after dosing through to the end of the experiment. Physiological measures did not change significantly before or after exposure to both pesticides; however, other indicators showed evidence of exposure, which remained for the entirety of our monitoring period. On average, cholinesterase inhibition was still >30% compared with control lizards at the end of 4 weeks, and fipronil sulfone blood residues remained at 0.219 μg/ml. Our study provides novel insights into the impacts that common pesticides have on widespread lizard species. We show that an ecologically relevant low dose of fipronil alters the behaviour of P. vitticeps, which has the potential to impact longer-term survivability. Persistence of both pesticides in the blood of all treatment lizards throughout the experiment indicates they are unable to clear these toxins within a month of being exposed. This may be significant for compounding exposure and latent toxicity. These findings highlight the susceptibility that reptiles have to a selection of common pesticides and the inherent need for higher prominence in wildlife ecotoxicological research.

Project description:The SCN1A gene encodes the alpha subunit of a voltage-gated sodium channel (Nav1.1), which is essential for the function of inhibitory neurons in the brain. Mutations in this gene cause severe encephalopathies such as Dravet syndrome (DS). Upregulation of SCN1A expression by different approaches has demonstrated promising therapeutic effects in preclinical models of DS. Limiting the effect to inhibitory neurons may contribute to the restoration of brain homeostasis, increasing the safety and efficacy of the treatment. In this work, we have evaluated different approaches to obtain preferential expression of the full SCN1A cDNA (6 Kb) in GABAergic neurons, using high-capacity adenoviral vectors (HC-AdV). In order to favour infection of these cells, we considered ErbB4 as a surface target. Incorporation of the EGF-like domain from neuregulin 1 alpha (NRG1α) in the fiber of adenovirus capsid allowed preferential infection in cells lines expressing ErbB4. However, it had no impact on the infectivity of the vector in primary cultures or in vivo. For transcriptional control of transgene expression, we developed a regulatory sequence (DP3V) based on the Distal-less homolog enhancer (Dlx), the vesicular GABA transporter (VGAT) promoter, and a portion of the SCN1A gene. The hybrid DP3V promoter allowed preferential expression of transgenes in GABAergic neurons both in vitro and in vivo. A new HC-AdV expressing SCN1A under the control of this promoter showed improved survival and amelioration of the epileptic phenotype in a DS mouse model. These results increase the repertoire of gene therapy vectors for the treatment of DS and indicate a new avenue for the refinement of gene supplementation in this disease. KEY MESSAGES: Adenoviral vectors can deliver the SCN1A cDNA and are amenable for targeting. An adenoviral vector displaying an ErbB4 ligand in the capsid does not target GABAergic neurons. A hybrid promoter allows preferential expression of transgenes in GABAergic neurons. Preferential expression of SCN1A in GABAergic cells is therapeutic in a Dravet syndrome model.

Dataset Information

Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.

Publications

Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.

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