title: Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures.
abstract: BACKGROUND
  Human 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.
  
  
  RESULTS
  A 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
  The 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.
authors.affiliation: INSERM UMR 910, University of Méditerranée, Marseille, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jamali
authors.forename: Annick
authors.initials: A
authors.lastname: Salzmann
authors.forename: Nader
authors.initials: N
authors.lastname: Perroud
authors.forename: Magali
authors.initials: M
authors.lastname: Ponsole-Lenfant
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cillario
authors.forename: Patrice
authors.initials: P
authors.lastname: Roll
authors.forename: Nathalie
authors.initials: N
authors.lastname: Roeckel-Trevisiol
authors.forename: Ariel
authors.initials: A
authors.lastname: Crespel
authors.forename: Jorg
authors.initials: J
authors.lastname: Balzar
authors.forename: Kurt
authors.initials: K
authors.lastname: Schlachter
authors.forename: Ursula
authors.initials: U
authors.lastname: Gruber-Sedlmayr
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Pataraia
authors.forename: Christoph
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimprich
authors.forename: Fritz
authors.initials: F
authors.lastname: Zimprich
authors.forename: Alain
authors.initials: A
authors.lastname: Malafosse
authors.forename: Pierre
authors.initials: P
authors.lastname: Szepetowski
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003176:Complement C3 / Q000235:genetics*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D003294:Seizures, Febrile / Q000235:genetics*; D055815:Young Adult
chemical_list: D003176:Complement C3