Abstracts

Glio-neuronal lesions are frequently observed in biopsy specimens obtained from patients with pharmacoresistant epilepsies, comprising focal cortical dysplasias (FCD) and gangliogliomas. Recent findings characterize the phosphoinositide 3-kinase (PI3K) pathway and tuberin/hamartin signaling cascade to be compromized in these lesions. Ezrin, radixin and moesin (ERM-/band-4.1 proteins) genes represent downstream effectors of the PI3K-pathway, are involved in cytoskeleton-membrane interference, cell growth, migration and differentiation and harbor tumor suppressor motifs. Accumulation of band-4.1 proteins has been identified in cortical tubers of tuberous sclerosis patients, which share neuropathological similarities with FCD and gangliogliomas. We have studied the immunohistochemical distribution pattern of ERMs in gangliogliomas (n=20) and focal cortical dysplasias (FCD[sub]IIa[/sub], n=8; FCD[sub]IIb[/sub], n=37). Mutational screening of the ezrin and radixin genes was performed by PCR-SSCP and sequencing analyses. Aberrant accumulation of [italic]ERMs[/italic] was observed in dysplastic neurons of FCDs and gangliogliomas as well as in balloon cells. Adjacent brain tissue without structural abnormalities was used as control and showed only faint neuropil staining. Mutational screening revealed silent polymorphisms in the [italic]ezrin[/italic] gene in two individuals suffering from FCD[sub]IIb[/sub]. A transition from G to A of [italic]radixin[/italic] exon 2 resulted in an exchange of valine by isoleucine at codon 50 in an additional FCD[sub]IIb[/sub] specimen. These sequence alterations were not found in controls. The present data suggest accumulation of ERM expression in dysplastic cellular components but do not favor mutational events of ERM in the pathogenesis of FCDs or gangliogliomas. Aberrant expression of ERMs is, however, compatible with a compromised PI3K-pathway in glio-neuronal lesions characterized by abnormal cellular differentiation and aberrant network formation. (Supported by DFG (SFB TR3), BONFOR, Deutsche Krebshilfe and BMBF. We especially thank Professor Shoichiro Tsukita and colleagues for kindly providing antibodies against the ERM proteins.)