Focal cortical dysplasias (FCD) with Taylor-type balloon cells (FCD(IIb)) are frequently observed in biopsy specimens of patients with pharmacoresistant
focal epilepsies. The molecular pathogenesis of FCD(IIb), which lack familial inheritance, is only poorly understood. Due to their highly differentiated, malformative nature and glioneuronal phenotype, FCD(IIb) share neuropathological characteristics with lesions observed in familial disorders such as cortical tubers present in patients with autosomal dominant
tuberous sclerosis complex (
TSC), related to mutations in the TSC1 or TSC2 genes, and dysplastic
gangliocytomas of the cerebellum found in
Cowden disease. Current data have indicated distinct allelic variants of TSC1 to accumulate in FCD(IIb). TSC1 represents a
tumor suppressor operating in the
phosphatidylinositol 3-kinase (PI3K)/
insulin pathway. The tumor-suppressor gene PTEN is mutated in
Cowden disease. Like PTEN, also carboxyl-terminal modulator
protein (
CTMP) modulates PI3K-pathway signaling, both via inhibition of Akt/PKB, a
kinase inactivating the TSC1/TSC2 complex. Here, we have analyzed alterations of Akt, PTEN and
CTMP relevant for
insulin signaling upstream of TSC1/TSC2 in FCD(IIb). Immunohistochemistry with
antibodies against phosphorylated Akt (phospho-Akt; Ser 473) in FCD(IIb) (n=23) showed strong phospho-Akt expression in dysplastic FCD(IIb) components. We have further studied sequence alterations of PTEN (n=34 FCD(IIb)) and
CTMP (n=20 FCD(IIb)) by
laser microdissection/single-strand conformation polymorphism analysis. We observed a somatic mutation in an FCD(IIb), i.e.,
amino-acid exchange at
nucleotide position 834 (PTEN
cDNA, GenBank AH007803.1) in exon 8 with replacement of
phenylalanine by
leucine (F278L). We also found several silent polymorphisms of PTEN in exon 2 and exon 8 as well as silent and coding polymorphisms but no mutations in
CTMP. No loss of heterozygosity in FCD(IIb) (n=6) at 10q23 was observed. To our knowledge, we here report on the first somatic mutation of a tumor-suppressor gene, i.e., PTEN, in FCD(IIb). However, our study also demonstrates that mutational alterations of PTEN and
CTMP do not play major pathogenetic roles for activation of Akt in FCD(IIb). Future studies need to determine the origin of
insulin pathway activation upstream of TSC1/TSC2 in FCD(IIb).