Résumé
Objective To investigate the relationship between the single nucleotide polymorphisms of SCN1A genes and the therapeutic effects of carbamazepine in Zhuang population with epilepsies. Methods We used Mass ARRAY-IPLEX and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) technology to detect the SCN1A gene rs4667869 and rs10497275 genotypes in peripheral blood of186 Zhuang individuals with epileptic (66 cases in effective group and 120 cases of ineffective group) who received the standardized treatment of carbamazepine in Baise Region. The reversed phase high-performance liquid chromatography was used to determine blood drug level of carbamazepine. The correlations between the genotypes, alleles and the carbamazepine efficacy of the two groups were evaluated, respectively. We also analyzed the difference of carbamazepine's blood concentration between different genotypes. Results Three genotypes of GG, GC and CC were detected in rs4667869 locus. There were 3 genotypes of GG, GA and AA found in rs 10497275 locus.The differences in the allele distribution (χ2 = 11.790, P = 0.001) and genotype distribution (χ2= 10.655, P =0.005) of the rs4667869 locus were statistically significant between the two groups (ineffective group vs. effective group). However, there was no significant difference in allele distribution (χ2 = 3.335, P= 0.068) and genotype (χ2= 3.046, P = 0.218) for rs 10497275 locus in these two groups. Compared with the GG + GC genotype, the CC genotype of rs4667869 locus significantly reduced the antiepileptic efficacy of carbamazepine (OR = 2.800, 95％CI : 1.495～5.244). W hile there were no significant differences in blood concentration of genotype CC (t=1.273, P = 0.083) comparing with genotypes GG + GC in rs4667869. No significant differences were found in blood concentration between genotype AA and genotypes GG + GA of rs 10497275 (t= 0.963, P = 0.064). Conclusions These results suggest that the single nucleotide polymorphisms of rs4667869 in SCN1A genes could be associated with the drug resistance of carbamazepine in Zhuang population with epilepsies.
Résumé
Objective To determine the role of SCN1A gene variation in the development of familial febrile seizures (FS).Methods Clinical data were collected from 8 familial FS pedigrees, and peripheral venous blood samples were collected from the probands and other available family members. All 26 coding exons and exon-intron boundaries at least 50 bases of the human SCN1A gene were amplifled by polymerase chain reaction, the products were subsequently sequenced. To novo variation, other family members were screened for the corresponding exons. Two hundred age-matched healthy children were served as normal controls. ResultsA total of 33 variations in the SCN1A gene were identifled in these families. Of these variations, one was a missense mutation; the remaining 32 variations were previously submitted as single nucleotide polymorphisms (SNPs). A c.2650G>A heterozygous missense mutation in exon 15 of the SCN1A gene found in the proband of family 4 was inherited from his father who had seizures with fever in early childhood. The c.2650G>A mutation was absent in the 400 alleles of normal controls. To the best of our knowledge, the SCN1A c.2650G>A mutation has neither been reported in the NCBI SNP database nor in the literature to date. The c.2650G>A mutation changes a glycine at amino acid 884 in the SCN1A protein to a serine (p.Gly884Ser). Protein sequence analysis showed that the p.Gly884Ser is located at a highly conserved region between the 4th and 5th transmembrane segment of the homologous domain Ⅱ of voltage-gated sodium channel 1 subunit (DIIS4-S5). ConclusionsThe pathogenesis of familial febrile seizures was related to the SCN1A variation, the mutation outside the region of the voltage sensor (S4) and ion channel pore (S5-S6) of the voltage gated sodium channelα-subunit may be an important factor to cause mild phenotype epilepsy syndrome.