A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.
We recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multiplex families and 61 sporadic cases. The novel mutation W1204R was identified in a family with GEFS+. Seven other coding changes were observed; three of these are potential disease-causing mutations. Two common haplotypes, with frequencies of .67 and .33, were defined by five single-nucleotide polymorphisms (SNPs) spanning a 14-kb region of linkage disequilibrium. An SNP located 18 bp upstream of the splice-acceptor site for exon 3 was observed in 7 of the 226 patients but was not present in 185 controls, suggesting possible association with a disease mutation. This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family. Although a few candidate disease alleles were identified, the patient survey suggests that SCN1A is not a major contributor to idiopathic generalized epilepsy. The SCN1A haplotypes and SNPs identified here will be useful in future association and linkage studies.
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
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A
Escayg
A
A
Heils
B T
BT
MacDonald
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K
Haug
T
T
Sander
M H
MH
Meisler
D000595:Amino Acid Sequence; D017124:Conserved Sequence / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics*; D004829:Epilepsy, Generalized / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D003294:Seizures, Febrile / Q000235:genetics*; D016415:Sequence Alignment; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases