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. 2001 Jun;68(6):1327-32.
doi: 10.1086/320609. Epub 2001 May 15.

De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy

L Claes  1 , J Del-Favero, B Ceulemans, L Lagae, C Van Broeckhoven, P De Jonghe
Affiliations

De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy

L Claes et al. Am J Hum Genet. 2001 Jun.

Abstract

Severe myoclonic epilepsy of infancy (SMEI) is a rare disorder that occurs in isolated patients. The disease is characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Later, patients also manifest other seizure types, including absence, myoclonic, and simple and complex partial seizures. Psychomotor development stagnates around the second year of life. Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ is a mild type of epilepsy associated with febrile and afebrile seizures. Because both GEFS+ and SMEI involve fever-associated seizures, we screened seven unrelated patients with SMEI for mutations in SCN1A. We identified a mutation in each patient: four had frameshift mutations, one had a nonsense mutation, one had a splice-donor mutation, and one had a missense mutation. All mutations are de novo mutations and were not observed in 184 control chromosomes.

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Figures

Figure 1
Figure 1
Organization of SCN1A. The neuronal voltage-gated sodium-channel α-subunit SCN1A is a monomer and consists of four homologous domains (DI–DIV). Each domain has six transmembrane segments (S1–S6). S4 has several positively charged amino acids and represents the voltage sensor. P = the pore loop, which delineates the pore of the channel. Mutations identified in this study (described in table 2) were denoted as follows: asterisks (*) = deletion, insertion and nonsense mutations; diamond (♦) = missense mutation; circles (●) = GEFS+ missense mutations reported by Escayg et al. (2000, 2001); and squares (▪) = GEFS+ missense mutations reported by Wallace et al (2001).
Figure 2
Figure 2
Chromatograms of the SCN1A mutations in comparison with SCN1A wild-type sequences. Exonic sequences are in uppercase; intronic sequences are in lowercase.
Figure 3
Figure 3
Evolutionary conservation of SCN1A. Sequence alignment and evolutionary conservation of the 986L residue (boxed).
See this image and copyright information in PMC

References

Electronic-Database Information

    1. Genbank, http://www.ncbi.nlm.nih.gov/Genbank (for genomic clone containing SCN1A [accession number AC010127], human SCN1A [for cDNA accession number AF225985, for protein accession number AAK00217], Rattus norvegicus Scn1a [accession number AAA79965], human SCN2A [accession number NP_066287], human SCN3A [accession number AAK00219], Rattus norvegicus Scn3a [accession number NP_037251], human SCN4A [accession number NP_000325], human SCN5A [accession number NP_000326], human SCN6A [accession number NP_002967], human SCN8A [for cDNA accession number XM_006838, for protein accession number XP_006838], human SCN9A [accession number NP_002968], human SCN10A [accession number NP_006505], human SCN11A [accession number AAF17480], human SCN12A [accession number NP_054858], Takifugu rubripes [accession number BAA07195], Loligo opalescens [accession number AAA16202], Electrophorus electricus [accession number CAA25587], Drosophila melanogaster [accession number AAB59192])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for GEFS+ [MIM 604233]) - PubMed
    1. Primer3 program, http://www.genome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi
    1. CEPH genotype database, http://www.cephb.fr/cephdb/dumps.html

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