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| Author(s): |
Simone Sayuri Tsuneda
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2007-02-26 |
| Examining board members: |
Íscia Teresinha Lopes Cendes;
João Pereira Leite;
Marilisa Mantovani Guerreiro
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| Advisor: | Íscia Teresinha Lopes Cendes |
| Abstract | |
Epilepsy is a very frequent condition, been present in around 0.5 to 1% of human population. Among the most frequent causes of epilepsy we can identify genetic predisposition to seizures and cortical malformations. The idiopathic epilepsies are regarded as caused by genetic mechanisms, most of them with no structural abnormalities being detected. By the other hand, malformations of cortical development (MCD) are the result of abnormalities during the normal developmental stages of the brain and will generally result in identifiable brain structural abnormalities. We studied patients with a form of temporal lobe named autosomal dominant partial epilepsy with auditory features (ADPEAF) and identified a splicing site mutation in the LGI1 gene. In addition, we identified a point mutation in the FLN1 gene in two patients (mother and daughter) with a type of MCD, periventricular nodular heterotopia. The main objective of this project was to characterize the molecular defect resulting from both mutations, as well as to investigate if these mechanisms could explain the clinical variability observed in our patients. We extracted mRNA from patients carrying both mutations for subsequent synthesis of cDNA. In patients with FLN1 mutation mRNA was obtained from peripheral blood and in patients with LGI1 mutation mRNA extractions were attempted from skin fibroblasts. Our results indicate that the molecular mechanism involved in the FLN1 1159G?C mutation is probably the destruction of the splicing donor site at intron 6, leading to the its transcription during mRNA processing, which, in turn, will add a premature stop codon resulting in a truncated protein. Unfortunately we were unable to obtain conclusive results in the LGI1 experiments. In addition, in silico prediction studies o the truncated FLNI1 protein shows that important functional domains are lost in the resulting mutated form. Furthermore, we found experimental evidence that the clinical variability observed in the two patients with FLN1 mutation could be explained, at least in part, by abnormal skewed X chromosome inactivation (AU) | |