Rapid communicationMissense mutation of the sodium channel gene SCN2A causes 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
References (14)
- et al.
Truncation of the GABAA-receptor γ2 subunit in a family with generalized epilepsy with febrile seizures plus
Am J Hum Genet
(2002) A catalog of SCN1A variants
Brain Dev
(2009)- Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology...
A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology
Epilepsia
(2001)- et al.
Microchromosomal deletions involving SCN1A and adjacent genes in severe myoclonic epilepsy in infancy
Epilepsia
(2008) - et al.
Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients
J Med Genet
(2009) - et al.
A missense mutation of the Na+ channel αII subunit gene Nav1.2 in a patient with febrile and afebrile seizures causes channel dysfunction
Proc Natl Acad Sci USA
(2001)
Cited by (98)
Seizures as the first manifestation of chromosome 2q24.2-q24.3 in a two and a half years old girl: A case report
2021, Gynecology and Obstetrics Clinical MedicineGenetics and clinical correlation of Dravet syndrome and its mimics – experience of a tertiary center in Taiwan
2021, Pediatrics and NeonatologyNew avenues in molecular genetics for the diagnosis and application of therapeutics to the epilepsies
2021, Epilepsy and BehaviorPatient-derived iPSC modeling of rare neurodevelopmental disorders: Molecular pathophysiology and prospective therapies
2021, Neuroscience and Biobehavioral ReviewsVenom-derived modulators of epilepsy-related ion channels
2020, Biochemical PharmacologyThe phenotypic spectrum of SCN2A-related epilepsy
2020, European Journal of Paediatric Neurology