Elsevier

Brain and Development

Volume 31, Issue 10, November 2009, Pages 758-762
Brain and Development

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Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome

https://doi.org/10.1016/j.braindev.2009.08.009Get rights and content

Abstract

Mutations of the gene encoding the α2 subunit of the neuronal sodium channel, SCN2A, have been found in benign familial neonatal-infantile seizures (BFNIS). In Dravet syndrome, only one nonsense mutation of SCN2A was identified, while hundreds of mutations were found in the paralogue gene, SCN1A, which encodes the α1 subunit. This study examines whether SCN2A mutations are associated with Dravet syndrome. We screened for mutations of SCN1A, SCN2A and GABRG2 (the gene encoding γ2 subunit of the GABAA receptor) in 59 patients with Dravet syndrome and found 29 SCN1A mutations and three missense SCN2A mutations. Among the three, one de novo SCN2A mutation (c.3935G>C: R1312T) identified in a patient was thought to affect an arginine residue in a voltage sensor of the channel and hence, to be pathogenic. This finding suggests that both nonsense mutations and missense SCN2A mutations cause Dravet syndrome.

Introduction

Dravet syndrome, which includes severe myoclonic epilepsy in infancy (SMEI) and its borderline phenotype (SMEB), is a rare and malignant epilepsy syndrome, which usually develops in the first year of life [1], [2]. The majority of the genetic abnormalities underlying Dravet syndrome have been found in SCN1A, though a few mutations were found in GABRG2 [3]. To date, more than 300 different mutations of SCN1A have been reported [4]. Moreover, microchromosomal deletions involving SCN1A have been reported as a cause of Dravet syndrome [5]. Still, more than 20% patients with Dravet syndrome are free from such genetic abnormalities [6]. Further genetic studies are needed to determine other causative or associative genetic abnormalities in Dravet syndrome (i.e., SCN2A).

Both SCN1A and SCN2A are clustered within 600 kb on human chromosome 2q24. The first SCN2A mutation was reported in a patient with febrile and afebrile seizures similar to those of generalized epilepsy with febrile seizures plus (GEFS+) [7]. Subsequent studies have identified eight different mutations of SCN2A in benign familial neonatal-infantile seizures (BFNIS) [8]. Until now, all SCN2A mutations identified in BFNIS were missense mutations inherited from a single parent; each demonstrated impairment of the function of the sodium channel bearing α2 subunit or NaV1.2. Only one nonsense mutation of SCN2A, however, has been reported in patients with Dravet syndrome [9]. The aim of this study is to examine whether SCN2A mutations are associated with Dravet syndrome.

Section snippets

Patients

This study included 59 Japanese patients who had been diagnosed with Dravet syndrome (SMEI n = 33 and SMEB n = 26) at departments of child neurology in various regional tertiary hospitals. The diagnoses of SMEI and SMEB were made by the method described previously [10]. We also recruited 96 healthy volunteers as the control group. Each participant or the parent/guardian signed an informed consent form approved by the Ethics Review Committee of Fukuoka University or similar committees of the

Results

A total of 29 SCN1A mutations were found; none were found in GABRG2. Three novel missense mutations of SCN2A were identified in 3 (Table 1, 5.1%) of 59 patients but were not found in the 96 healthy volunteers.

Patient A with SMEI had a missense mutation of SCN2A (c.964G>A: D322N, exon 6, Fig. 1) and a splice site mutation of SCN1A (IVS4+1G>A), the mother had same mutation of SCN2A. Patient B with SMEB had missense mutations of SCN2A (c.982T>G: F328V, exon 7, Fig. 1) and SCN1A (c.4507G>A:

Discussion

This study reports three novel missense mutations of SCN2A in three Dravet syndrome patients who have no neonatal seizures. All three mutations affect highly conserved amino acids in many species. Two SCN2A mutations, c.964G>A: D322N and c.982T>G: F328V, however, coexisted with de novo SCN1A mutations, IVS4+1G>A and c.4507G>A: E1503K in patients with SMEI and SMEB, respectively. These mutations were also inherited from one of their parents and accordingly were not likely to be pathogenic. In

Acknowledgment

We are indebted to all members of the family for their helpful cooperation in this study. We thank Ms. Takako Umemoto and Hideko Takeda for formatting and typing the manuscript and Ms. Minako Yonetani and Akiyo Hamachi for the technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research (S) 16109006, (A) 18209035 and 21249062, Exploratory Research 1659272, and “High-Tech Research Center” Project for Private Universities-matching fund subsidy from the Ministry

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