Estudo de mutações em genes responsaveis por diferentes formas de disturbios do desenvolvimento cortical

AUTOR(ES)
DATA DE PUBLICAÇÃO

2003

RESUMO

Cortical development malformations (CDM) are one of the most important causes of epilepsy and developmental delay. Extensive molecular genetic studies have resulted in gene discovery for CDM such as periventricular nodular heterotopia (PNH), lisencephaly/ subcortical band heterotopia spectrum (LIS/SBH) and schizencephaly. The main goals of this project were 1) to screen for mutations in the four main genes responsible for abnormal cortical development (FLN1, LIS1, DCX and EMX2) in a large cohort of patients with different types of cortical malformations and 2) to perform phenotype-genotype correlations. All patients included in this study had CT scans or high resolution MRI scans. We have divided our patients in three groups: a) individuals with nodular heterotopia, b) individuals with the LIS/HSB spectrum and c) individuals with schizencephaly. Mutation screening was performed by the polymerase chain reactions (PCRs). PCR products were analyzed by single strand conformation polymorphism (SSCP) and were subsequently sequenced using standard manual sequencing or an automatic sequencer. We have studied a total of 58 patients with CMDs. Nine had nodular heterotopia, 15 had the LIS/HSB spectrum and 34 individuals had schizencephaly. In the group of nodular heterotopias we have detected a 1159G®C mutation in the FLN1 gene in two related patients with classical HNP and a neutral variant IVS5 + 519C®G in three patients (1 with typical and 2 with atypical imaging findings). In the LIS/SBH group 7 patients had a 1805C® T substitution in the beginning of the untranslated 3 region that is also present in 9 control individuals. One patient with agyria/pachygyria had a 1385A®C transversion which changes a histidine for a proline in amino acid 277 of the LIS1 protein. Furthermore, We detected a rare polymorphism in the DCX gene, a IVSV+19G®A, in a female with agyria/pachygyria. In the group of the schizencephalies we have detected 4 individuals with a 796A®C substitution that does not change the identity of the wild type arginine. The same alteration was found in 4 individuals of the control group. We conclude that: a) patients with atypical PNH do not have mutations in the first six coding exons of the FLN1 gene and there is a high incidence of FLN1 mutations in classical familial PNH; b) missense mutations in the LIS1 gene are a rare finding in patients with the LIS/SBH spectrum and its localization in latter WD domains are not always related with less severe LIS; c) the substitution 1805C®T is the same polymorphism previously described by KOCH et al. (1996); d) the absence of mutations in the DCX gene in patients with SBH could be explained by our small sample of patients with this pattern of malformation, somatic mosaicism or low stringency for the neuroimage findings; e) the substitution IVSV+19G®A found in the DCX gene is a rare polymorphism (idiomorphism) f) schizencephalies appear not to have genetic background in the EMX2, since our study detected only a neutral polymorphism in these patients

ASSUNTO(S)

genetica cortex cerebral sistema nervoso central

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