A RIKEN-led research team has gathered strong biological evidence that mutations in the gene EFHC1 trigger the onset of a common form of adolescent epilepsy for which there is currently no explanation. The mutations also increase susceptibility to epileptic seizures. The gene encodes myoclonin1, a protein found in adults in cilia—the hair-like projections that line the windpipe and the ventricles or cavities in the brain. During development, myoclonin1 is also found in the cells that produce the cerebrospinal fluid in the ventricles. EFHC1 is one of the few genes known to be directly involved in the onset of epilepsy that does not code for a protein associated with the ion channels or pores in the plasma membrane. The researchers hope their findings can one day be translated into better treatment of juvenile myoclonic epilepsy.
The research group, led by Kazuhiro Yamakawa of RIKEN’s Brain Science Institute in Wako, had previously found an association between EFHC1 mutants and epilepsy. It had also determined the tissues in which myoclonin1 was produced. While work by other groups supported these findings, there was no direct biological or physiological evidence that EFHC1 deficiency caused epilepsy. Details of how the researchers gathered that evidence were recently published in Human Molecular Genetics1.
Initially, the researchers generated Efhc1-deficient mice (Fig. 1). These mutant mice appeared normal and were fertile both in the null form where two copies of the Efhc1 gene were defective and in the heterozygous form that carried only one defective copy. As they grew, however, mice of both forms began to display increased levels of the involuntary muscle twitches known as myoclonus, and both began to show increased susceptibility to a chemical known to trigger epileptic seizures.
When the researchers investigated the impact of Efhc1 deficiency on the null form they found enlarged ventricles in the brain and a reduced beating frequency of the cilia—both of which suggested that the onset of epilepsy may have something to do with the circulation of cerebrospinal fluid. But in the heterozygous form, neither of these two abnormalities was apparent, yet the mice showed the same susceptibility to development of epilepsy.
“So we don’t yet have a clear picture of the pathological cascade or mechanism,” says Yamakawa. “But in the knockout mouse we have provided a very important tool to investigate this further. Our next step is to clarify the pathological cascade. That would make a huge contribution to our understanding.”
Reference
1. Suzuki, T., Miyamoto, H., Nakahari, T., Inoue, I., Suemoto, T., Jiang, B., Hirota, Y., Itohara, S., Saido, T.C., Tsumoto, T. et al. Efhc1 deficiency causes spontaneous myoclonus and increased seizure susceptibility. Human Molecular Genetics 18, 1099–1109 (2009).
The corresponding author for this highlight is based at the RIKEN Laboratory for Neurogenetics
