Deletions of SCN1A 5′ genomic region with promoter activity in Dravet syndrome

Nakayama, Tojo; Ogiwara, Ikuo; Ito, Koichi; Kaneda, Makoto; Mazaki, Emi; Osaka, Hitoshi; Ohtani, Hideyuki; Inoue, Yushi; Fujiwara, Tateki; Uematsu, Mitsugu; Haginoya, Kazuhiro; Tsuchiya, Shigeru; Yamakawa, Kazuhiro

doi:10.1002/humu.21275

Cited by 48 publications

(38 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The associated region harbours several alternative untranslated SCN1A exons (Martin et al , 2007; Nakayama et al , 2010). We did not detect association between rs7587026 and any protein-coding exon except one (see below) or total SCN1A expression, or with expression of untranslated 5’ exons 1a and 1b (Martin et al , 2007) (data not shown) in 78 patients and 78 control subjects.…”

Section: Resultsmentioning

confidence: 99%

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Kasperavičiūtė¹,

Catarino²,

Matarı́n³

et al. 2013

Brain

174

111

View full text Add to dashboard Cite

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

show abstract

Section: Resultsmentioning

confidence: 99%

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Kasperavičiūtė¹,

Catarino²,

Matarı́n³

et al. 2013

Brain

174

111

View full text Add to dashboard Cite

show abstract

“…The reporter contained SCN1A promoter sequence [37], some SCN1A 5 ′ -untranslated region, as well as Venus cDNA following the ATG start codon (Figure 3A). This SCN1A -Venus construct was used to infect freshly plated cells from dissociated neurospheres.…”

Section: Resultsmentioning

confidence: 99%

“…The upstream genomic sequence of an SCN1A 5 ′ -untranslated exon (previously referred to as “h1b” by Martin, et al[50], or “hB” by Nakayama, et al[37]) was used as SCN1A promoter sequence. The 1,200-bp sequence stretch showed strong promoter activity and was obtained from the patient’s genomic DNA.…”

Section: Methodsmentioning

confidence: 99%

A human Dravet syndrome model from patient induced pluripotent stem cells

et al. 2013

View full text Add to dashboard Cite

BackgroundDravet syndrome is a devastating infantile-onset epilepsy syndrome with cognitive deficits and autistic traits caused by genetic alterations in SCN1A gene encoding the α-subunit of the voltage-gated sodium channel Nav1.1. Disease modeling using patient-derived induced pluripotent stem cells (iPSCs) can be a powerful tool to reproduce this syndrome’s human pathology. However, no such effort has been reported to date. We here report a cellular model for DS that utilizes patient-derived iPSCs.ResultsWe generated iPSCs from a Dravet syndrome patient with a c.4933C>T substitution in SCN1A, which is predicted to result in truncation in the fourth homologous domain of the protein (p.R1645*). Neurons derived from these iPSCs were primarily GABAergic (>50%), although glutamatergic neurons were observed as a minor population (<1%). Current-clamp analyses revealed significant impairment in action potential generation when strong depolarizing currents were injected.ConclusionsOur results indicate a functional decline in Dravet neurons, especially in the GABAergic subtype, which supports previous findings in murine disease models, where loss-of-function in GABAergic inhibition appears to be a main driver in epileptogenesis. Our data indicate that patient-derived iPSCs may serve as a new and powerful research platform for genetic disorders, including the epilepsies.

show abstract

“…Heterozygous mutations in the SCN1A gene, which encodes a voltage-gated sodium channel α I subunit (Nav1.1), are associated with a wide spectrum of childhood epilepsies, including generalized epilepsy with febrile seizures [Mendelian Inheritance in Man (MIM) #604233], and Dravet syndrome (MIM #607208) (1–8). Dravet syndrome is an intractable epileptic encephalopathy characterized by early onset epileptic seizures, mental retardation, autistic behaviors, ataxia and increased risk of sudden unexpected death in epilepsy (SUDEP) (9,10).…”

Section: Introductionmentioning

confidence: 99%

Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome

Ogiwara¹,

Iwasato

Miyamoto

et al. 2013

Human Molecular Genetics

Self Cite

154

176

View full text Add to dashboard Cite

Dravet syndrome is a severe epileptic encephalopathy mainly caused by heterozygous mutations in the SCN1A gene encoding a voltage-gated sodium channel Nav1.1. We previously reported dense localization of Nav1.1 in parvalbumin (PV)-positive inhibitory interneurons in mice and abnormal firing of those neurons in Nav1.1-deficient mice. In the present study, we investigated the physiologic consequence of selective Nav1.1 deletion in mouse global inhibitory neurons, forebrain excitatory neurons or PV cells, using vesicular GABA transporter (VGAT)-Cre, empty spiracles homolog 1 (Emx1)-Cre or PV-Cre recombinase drivers. We show that selective Nav1.1 deletion using VGAT-Cre causes epileptic seizures and premature death that are unexpectedly more severe than those observed in constitutive Nav1.1-deficient mice. Nav1.1 deletion using Emx1-Cre does not cause any noticeable abnormalities in mice; however, the severe lethality observed with VGAT-Cre-driven Nav1.1 deletion is rescued by additional Nav1.1 deletion using Emx1-Cre. In addition to predominant expression in PV interneurons, we detected Nav1.1 in subpopulations of excitatory neurons, including entorhino-hippocampal projection neurons, a subpopulation of neocortical layer V excitatory neurons, and thalamo-cortical projection neurons. We further show that even minimal selective Nav1.1 deletion, using PV-Cre, is sufficient to cause spontaneous epileptic seizures and ataxia in mice. Overall, our results indicate that functional impairment of PV inhibitory neurons with Nav1.1 haploinsufficiency contributes to the epileptic pathology of Dravet syndrome, and show for the first time that Nav1.1 haploinsufficiency in excitatory neurons has an ameliorating effect on the pathology.

show abstract

Deletions of SCN1A 5′ genomic region with promoter activity in Dravet syndrome

Cited by 48 publications

References 53 publications

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

A human Dravet syndrome model from patient induced pluripotent stem cells

Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome

Contact Info

Product

Resources

About