Zhou Xi-hui, Ma Ai-qun, Liu Xiao-hong, Huang Chen, Zhang Yan-min, Shi Rui-ming
Department of Pediatrics, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710061, China.
Zhonghua Er Ke Za Zhi. 2006 Jul;44(7):487-91.
Benign familial infantile convulsions (BFIC) is a form of idiopathic epileptic syndrome characterized by onset of afebrile seizures between 3 and 12 months of life, Spontaneous remission after several weeks or months, and autosomal dominant mode of inheritance. Previous linkage analysis in western countries defined three susceptible loci on chromosomes 19q12.0-13.1, 16p12-q12, and 2q23-31, but studies performed in several Chinese families with BFIC got negative results of these previously reported loci. The authors investigated the relation of voltage-gated potassium channel gene KCNQ2 to BFIC in a Chinese family and thus to understand the molecular pathogenesis of BFIC.
A four-generation Chinese BFIC family was investigated. All the affected 17 members had similar pattern of seizures starting from 2 to 6 months of age. In 15 of them, the seizures disappeared spontaneously within the first year of life. The phenotype extended beyond infancy only in two patients. Blood sample was collected from the 41 family members and 75 unassociated normal individuals. Polymerase chain reaction (PCR)-DNA direct sequencing was performed to screen all exons and their flanking introns of KCNQ2 gene for mutation analysis. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to ascertain the co-segregation of genotype and phenotype and to exclude polymorphism.
PCR amplification and subsequent direct sequencing of KCNQ2 from the DNA of proband revealed a heterozygous guanine to thymine nucleotide exchange (G812T) in exon 5, leading to the substitution of glycine by valine at amino acid position 271 (G271V) of the predicted protein. The same mutation with a comparable localization has been previously described for KCNQ3 in benign familial neonatal convulsions (BFNC). The glycine at this position (G271) is located in pore region of KCNQ2 protein and is evolutionarily highly conserved. The same SSCP variant as that of the proband was shown in the rest of the affected members of this family but not in the unaffected members enrolled in the study of this family and all the 75 unrelated normal individuals.
Previously reported mutations of KCNQ2 were mainly identified in BFNC family in which at least one individual had an onset of seizures during the first week of life, a hallmark of the BFNC disorder. The results of the present study suggest the possibility that KCNQ2 mutation exist in patients with BFIC diagnosis. G812T of KCNQ2 gene is a novel mutation found in BFIC and functional expression of KCNQ2 G812T is required for understanding the mechanism of BFIC and other idiopathic epilepsy.
良性家族性婴儿惊厥（BFIC）是一种特发性癫痫综合征，其特征为在出生后3至12个月出现无热惊厥，数周或数月后自发缓解，且呈常染色体显性遗传模式。西方国家先前的连锁分析在19号染色体19q12.0 - 13.1、16号染色体16p12 - q12和2号染色体2q23 - 31上确定了三个易感基因座，但在中国几个BFIC家系中进行的研究对这些先前报道的基因座得到了阴性结果。作者研究了电压门控钾通道基因KCNQ2与一个中国家系中BFIC的关系，从而了解BFIC的分子发病机制。
对一个四代中国BFIC家系进行研究。所有17名受累成员都有相似的惊厥发作模式，始于2至6个月大时。其中15人在出生后第一年内惊厥自发消失。仅两名患者的表型超出婴儿期。从41名家庭成员和75名无血缘关系的正常个体采集血样。采用聚合酶链反应（PCR）-DNA直接测序法筛查KCNQ2基因的所有外显子及其侧翼内含子以进行突变分析。采用聚合酶链反应-单链构象多态性（PCR-SSCP）来确定基因型和表型的共分离并排除多态性。
对先证者DNA进行KCNQ2的PCR扩增及后续直接测序，发现在第5外显子中有一个杂合的鸟嘌呤到胸腺嘧啶核苷酸交换（G812T），导致预测蛋白的第271位氨基酸（G271）处的甘氨酸被缬氨酸替代。先前在良性家族性新生儿惊厥（BFNC）中已描述过KCNQ3有相同定位的相同突变。该位置的甘氨酸（G271）位于KCNQ2蛋白的孔区，在进化上高度保守。该家系其余受累成员显示出与先证者相同的SSCP变异，但在参与该家系研究的未受累成员以及所有75名无血缘关系的正常个体中未显示。
先前报道的KCNQ2突变主要在BFNC家系中鉴定出，其中至少有一个个体在出生后第一周内出现惊厥发作，这是BFNC疾病的一个标志。本研究结果提示BFIC诊断患者中存在KCNQ2突变的可能性。KCNQ2基因的G812T是在BFIC中发现的一个新突变，需要对KCNQ2 G812T进行功能表达研究以了解BFIC和其他特发性癫痫的机制。
