The high incidence of epilepsy in humans places this disorder among the most common neurological conditions. It is therefore not surprising that many different causes underlie the appearance of seizures. Epilepsy is sometimes related to developmental abnormalities or brain injury. Other forms of epilepsy have a more subtle genesis and can be traced to genetic defects. Indeed, mutations in single genes can lead to abnormal neuronal firing and the development of convulsions. So far, the culprits in every case of non-symptomatic monogenic epilepsy have been mutations in ion channel genes. Now, Skradski et al. report an important exception to this rule: the identification of Mass1 (monogenic audiogenic seizure susceptible 1), a gene that encodes a protein with no homology to any known ion channel, which, when mutated, leads to the appearance of audiogenic seizures in mice.

Skradski et al. studied a strain of mouse susceptible to audiogenic seizures that has been known for 50 years — the Frings mouse. The phenotype of Frings mice had been traced to a single gene on chromosome 13 — Mass1 — and the authors used positional cloning techniques to identify and characterize this locus in detail. They found that Mass1 encodes a protein predicted to have multiple transmembrane domains, but no significant similarity to any ion channel or to other proteins. Only two motifs from Mass1 shared homology with other molecules — a sequence present in several sodium/calcium exchangers and a multicopper oxidase consensus site. Although both motifs provide some clues as to the nature of Mass1, its actual function will require the biochemical analysis of the protein, a task that promises to be daunting, as the Mass1 transcript seems to be expressed at very low levels.

The authors also analysed different strains of mice and identified several polymorphisms in Mass1 that could account in principle for the epilepsy observed in the Frings mutants. However, they found a strong correlation between a deletion at the carboxy-terminal tail of the protein and the presence of audiogenic seizures, pointing to this mutation as the best candidate to explain the phenotype.

It will now be interesting to investigate the effect of mutations in the human orthologue of Mass1. Intriguingly, the human gene is located in the vicinity of two noteworthy loci: FEB4 , which has been mapped in people with febrile convulsions, and USH2C , which has been mapped in patients with Usher syndrome 2C (a condition characterized by deafness and retinitis pigmentosa).