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Activation of Akt independent of PTEN and CTMP tumor-suppressor gene mutations in epilepsy-associated Taylor-type focal cortical dysplasias

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Abstract

Focal cortical dysplasias (FCD) with Taylor-type balloon cells (FCDIIb) are frequently observed in biopsy specimens of patients with pharmacoresistant focal epilepsies. The molecular pathogenesis of FCDIIb, which lack familial inheritance, is only poorly understood. Due to their highly differentiated, malformative nature and glioneuronal phenotype, FCDIIb 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 FCDIIb. 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 FCDIIb. Immunohistochemistry with antibodies against phosphorylated Akt (phospho-Akt; Ser 473) in FCDIIb (n = 23) showed strong phospho-Akt expression in dysplastic FCDIIb components. We have further studied sequence alterations of PTEN (n = 34 FCDIIb) and CTMP (n = 20 FCDIIb) by laser microdissection/single-strand conformation polymorphism analysis. We observed a somatic mutation in an FCDIIb, 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 FCDIIb (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 FCDIIb. However, our study also demonstrates that mutational alterations of PTEN and CTMP do not play major pathogenetic roles for activation of Akt in FCDIIb. Future studies need to determine the origin of insulin pathway activation upstream of TSC1/TSC2 in FCDIIb.

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Acknowledgments

Our work is supported by Deutsche Forschungsgemeinschaft (SFB TR3; AJB, MM, CEE), Deutsche Krebshilfe (Deutsches Gliomnetz; MS), Bundesministerium fuer Bildung und Forschung (German–Israeli collaborative research program; AJB) and the BONFOR program of the University of Bonn Medical Center (MM, GE).

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Authors and Affiliations

  1. Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Volker Schick, Michael Majores, Gudrun Engels, Sylvia Spitoni, Arend Koch & Albert J. Becker

  2. Department of Epileptology, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Christian E. Elger

  3. Department of Neurosurgery, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Matthias Simon

  4. Department of Neuropathology, University of Düsseldorf, Dusseldorf, Germany

    Christiane Knobbe

  5. Department of Neuropathology, University of Erlangen, Erlangen, Germany

    Ingmar Blümcke

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  1. Volker Schick
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Correspondence to Albert J. Becker.

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Schick, V., Majores, M., Engels, G. et al. Activation of Akt independent of PTEN and CTMP tumor-suppressor gene mutations in epilepsy-associated Taylor-type focal cortical dysplasias. Acta Neuropathol 112, 715–725 (2006). https://doi.org/10.1007/s00401-006-0128-y

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