Abstract

BackgroundHuman mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE.Methodology/Principal FindingsA case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS.Conclusions/SignificanceThe present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy.

Highlights

  • The mammalian complement system is a key component of innate immunity and participates in adaptive immunity

  • The GF100472 allele (CA)11 contained within HAP5, was protective by itself in a replication study composed by novel series of febrile seizures (FS) patients and controls

  • HAP4 did not show any significant difference in an independent population of pure FS compared to matched controls

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Summary

Introduction

The mammalian complement system is a key component of innate immunity and participates in adaptive immunity It is composed of more than 30 plasma and cell surface proteins that interact in a very precise and regulated way[1]. Besides their canonical roles, there is increasing evidence that components of the complement system participate in various physiological processes of the central nervous system (CNS) such as synapse elimination during development[2] or adult neurogenesis[3]. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE make it the C3 gene a good candidate for human MTLE

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