In 1991, American Dianne Neale began to experience seizures when listening to the voice of "Entertainment Tonight" co-host Mary Hart.
Neale suffered from a rare condition called audiogenic epilepsy, in which specific sounds mysteriously trigger excessive discharges in the brain.
Audiogenic epilepsy is a subset of the broader class of reflex epilepsies which can be triggered by stimuli such as flashing lights, reading, writing, startle hot baths, difficult puzzles or simple math.
For the first time, a gene that could be responsible for an audiogenic form of reflex epilepsy has been mapped by Louis Ptácek and colleagues at the University of Utah in Salt Lake City. Their results are reported in today's issue of the journal Neuron.
Ptácek's group was working with a strain of mice called Frings, which carry a spontaneous mutation that causes them to have seizures in response to loud noise.
Earlier genetic mapping studies had shown that unlike other genetically more complex mouse models of sound-induced epilepsy which have mutations at multiple sites, the inherited mutation in the Frings mouse could be mapped to a single locus named mass1 on chromosome 13.
In humans, there is an analog of this gene on chromosone 5 at a site implicated in some families with genetic epilepsy. So the team decided to map the mutation in the mass1 locus in detail and to identify the nature of the protein in order to cast light on the epileptic disorder.
Most genetic epilepsies are related to mutations in genes coding for proteins called ion channels that are responsible for regulating the flow of ions in the brain.
As communication between nerve cells in the brain is largely dependent on electrical signals carried by ion flow, problems with these channels could explain the electric discharges that accompany an epileptic seizure.
In the case of the Fring's mouse mutation though, the team found that mass1 codes for a novel protein that does not seem to be related to ion channels. Instead, the novel mass1 protein belongs to a family of proteins that oxidize and transport iron and other metals.
Without a working version of the protein, it may be difficult to process neurotransmitters that rely on metal transport. The identification of the mass1 mutation and protein is significant for defining the first naturally occurring genetic defect responsible for reflex epilepsy and promises to yield unique insights into the mechanism of this rare form of inherited seizure disorders.
Already, a cursory examination of the human genetic databases reveals two interesting syndromes that map genetically to the vicinity of the human mass1 locus: familial febrile convulsions and the deafness-associated Usher syndrome type 2C. With its relationship to both seizures and auditory signalling, human Mass1 might be considered a viable candidate for either condition.
In a related preview, Daniel Burgess of the Baylor College of Medicine in Houston discusses the potential functional roles of the mass1 protein and lays out the important future questions in determining how mutations at this locus lead to audiogenic epilepsy.
[Contact: Louis Ptácek, Daniel L. Burgess]