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.%目的 探讨SCN1A基因变化在家族性热性惊厥发病中的作用.方法 收集8个家族性热性惊厥家系的临床资料,留取先证者和部分家系成员的血液标本,PCR扩增所有先证者SCN1A基因编码的26个外显子及其上下游侧翼序列至少50个以上碱基,并测序.对新发现的碱基变化,再对家系其他成员进行相应外显子的基因序列筛查,从而明确变异起源.同时纳入200例同年龄正常对照者加以验证.结果 8例先证者存在33种碱基变化,其中32种被提交为单核苷酸多态性,一处为新发现的错义突变.家系4先证者第15外显子存在一错义突变(C.2650 G>A),该碱基变化尚未见报告,且证实突变遗传自先证者父亲.200名正常对照者相应外显子测序未发现该碱基变化.C.2650 G>A导致SCN 1 A第884位的甘氨酸为丝氨酸所替代(Gly 884 Ser).突变位于电压门控钠离子通道α亚基第2同源结构域的第4次跨膜和第5次跨膜之间(DIIS 4-S 5),通过蛋白序列比对,该氨基酸高度保守.结论 SCN1A基因突变与家族性热性惊厥的发病有关,电压门控钠离子通道α亚基电压感受器(S 4)及离子通道孔(S 5-S 6)外区突变可能是引起表型相对较轻的癫痫综合征的重要原因.
展开▼
