title: Distinct allelic variants of TSC1 and TSC2 in epilepsy-associated cortical malformations without balloon cells.
abstract: Epilepsy-associated malformations of cortical development (MCDs) comprise a variety of dysplastic and neoplastic lesions of yet undetermined molecular pathology. Histopathologic similarities between MCDs and dysplastic brain lesions in the autosomal inherited neurocutaneous phacomatosis tuberous sclerosis (TSC), which affects the TSC1 and/or TSC2 genes, suggest common pathogenetic mechanisms. Previous studies revealed different alterations of TSC1 and TSC2 in epilepsy-associated malformations and glio-neuronal tumors despite histopathologic similarities. In order to examine current clinico-pathologic classification systems of cortical malformations on the molecular level, we carried out a mutational analysis of TSC1 and TSC2 in a series of surgical specimens obtained from patients with FCD without Taylor type balloon cells (FCDIIa; n = 20), architectural dysplasias (FCDI; n = 15), nodular cortical heterotopias (NCH; n = 4), and heterotopic white matter neurons (WMNH; n = 19). In FCDIIa, abundant genomic polymorphisms were detected in TSC2 (intron 4) but no allelic variants observed in exon 17 of TSC1. This allelic distribution pattern is in contrast to findings in FCDI and WMNH but also to those previously reported in FCDIIb (Taylor's balloon cell type). The latter revealed increased frequencies of specific alleles only in TSC1. The determination of characteristic molecular genetic alterations in specific epilepsy-associated malformations will support a comprehensive clinico-pathologic classification system and help to identify molecular pathways with potential pathogenetic relevance. Our work is supported by DFG (SFB TR3 [AJB], DFG Bl 421/1-1 [IB]), BONFOR, and Deutsche Krebshilfe.
authors.affiliation: Department of Neuropathology, Bonn University, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Majores
authors.forename: Ingmar
authors.initials: I
authors.lastname: Blümcke
authors.forename: Horst
authors.initials: H
authors.lastname: Urbach
authors.forename: Alessandra
authors.initials: A
authors.lastname: Meroni
authors.forename: Volkmar
authors.initials: V
authors.lastname: Hans
authors.forename: Hans
authors.initials: H
authors.lastname: Holthausen
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.forename: Carlo
authors.initials: C
authors.lastname: Galli
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.forename: Otmar D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001927:Brain Diseases / Q000150:complications / Q000151:congenital; D002540:Cerebral Cortex / Q000473:pathology*; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D014644:Genetic Variation; D006801:Humans; D007834:Lasers; D019656:Loss of Heterozygosity; D042282:Microdissection; D008969:Molecular Sequence Data; D009421:Nervous System Malformations / Q000145:classification* / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D012097:Repressor Proteins / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins