Nature Genetics
19, 366 - 370 (1998)
doi:10.1038/1252
Febrile seizures and generalized epilepsy associated with a mutation
in the Na+-channel  1 subunit gene SCN1BRobyn H. Wallace1, 2, Dao W. Wang3, Rita Singh4, 5, Ingrid E. Scheffer4, 5, 6, Alfred L. George Jr.3, Hilary A. Phillips1, Kathrin Saar7, Andre Reis7, 8, Eric W. Johnson9, Grant R. Sutherland1, 2, Samuel F. Berkovic4, 5
& John C. Mulley1, 101
Department of Cytogenetics and Molecular Genetics, Centre for Medical Genetics, Women's and Children's Hospital, North Adelaide, SA 5006, Australia. 2
Department of Paediatrics, University of Adelaide, Adelaide, Australia. 3
Departments of Medicine and Pharmacology, Centre for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. 4
Department of Medicine (Neurology), The University of Melbourne, Austin and Repatriation Medical Centre, Melbourne, Australia. 5
Department of Neurology, Royal Children's Hospital, Melbourne, Australia. 6
Neurosciences, Monash Medical Centre, Melbourne, Australia. 7
Mikrosatellitenzentrum, Max-Delbruk Zentrum, D-14059 Berlin, Germany. 8
Institute of Human Genetics, Humboldt University, Berlin, Germany. 9
Neurogenetics/Neuropharmacology, Centre for Medical Genetics, MMREF, Marshfield, Wisconsin 54449, USA. 10
Department of Genetics, University of Adelaide, Adelaide, Australia.
Correspondence should be addressed to John C. Mulley mulleyj@mail.wch.sa.gov.auFebrile seizures affect approximately 3% of all children under six
years of age and are by far the most common seizure disorder1.
A small proportion of children with febrile seizures later develop ongoing
epilepsy with afebrile seizures2. Segregation analysis suggests
the majority of cases have complex inheritance3 but rare families
show apparent autosomal dominant inheritance. Two putative loci have been
mapped (FEB1 and FEB2), but specific genes have not yet been
identified4,
5. We recently described a clinical subset, termed
generalized epilepsy with febrile seizures plus (GEFS+), in
which many family members have seizures with fever that may persist beyond
six years of age or be associated with afebrile generalized seizures6. We now report linkage, in another large GEFS+ family,
to chromosome region 19q13.1 and identification of a mutation in the voltage-gated
sodium (Na+)-channel 1 subunit gene (SCN1B).
The mutation changes a conserved cysteine residue disrupting a putative disulfide
bridge which normally maintains an extracellular immunoglobulin-like fold.
Co-expression of the mutant 1 subunit with a brain Na+-channel
subunit in Xenopus laevis oocytes demonstrates that the mutation
interferes with the ability of the subunit to modulate channel-gating kinetics
consistent with a loss-of-function allele. This observation develops the theme
that idiopathic epilepsies are a family of channelopathies and raises the
possibility of involvement of other Na+-channel subunit genes
in febrile seizures and generalized epilepsies with complex inheritance patterns.
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