Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures
| Autor: | Annick Salzmann, Nathalie Roeckel-Trevisiol, Jennifer Cillario, Ekaterina Pataraia, Christoph Baumgartner, Ariel Crespel, Alain Malafosse, Magali Ponsole-Lenfant, Jorg Balzar, Nader Perroud, Patrice Roll, Ursula Gruber-Sedlmayr, Pierre Szepetowski, Alexander Zimprich, Kurt Schlachter, Fritz Zimprich, Sarah Jamali |
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| Přispěvatelé: | Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU) |
| Rok vydání: | 2010 |
| Předmět: |
Male
[SDV]Life Sciences [q-bio] lcsh:Medicine Epilepsy ddc:616.89 0302 clinical medicine Polymorphism (computer science) Seizures Febrile/*genetics Genotype lcsh:Science Child Promoter Regions Genetic ComputingMilieux_MISCELLANEOUS Genetics and Genomics/Genetics of Disease Genetics 0303 health sciences education.field_of_study Multidisciplinary Complement C3 Child Preschool Female Research Article Adolescent Population Biology Polymorphism Single Nucleotide Seizures Febrile 03 medical and health sciences Young Adult Genetic variation Neurological Disorders/Epilepsy medicine Genetic predisposition Humans Genetic Predisposition to Disease Allele education 030304 developmental biology Epilepsy Temporal Lobe/*genetics Haplotype lcsh:R Genetic Variation medicine.disease nervous system diseases Epilepsy Temporal Lobe Neurological Disorders/Neurogenetics Case-Control Studies Complement C3/*genetics lcsh:Q 030217 neurology & neurosurgery Microsatellite Repeats |
| Zdroj: | PLoS ONE PLoS ONE, Public Library of Science, 2010, 5 (9), pp.e12740. ⟨10.1371/journal.pone.0012740⟩ PLOS ONE, Vol. 5, No 9 (2010) PLoS ONE, Vol 5, Iss 9, Pp 3307-3314 (2010) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0012740⟩ |
| Popis: | 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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. |
| Databáze: | OpenAIRE |
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