Singh Nanda A, Westenskow Peter, Charlier Carole, Pappas Chris, Leslie Jonathan, Dillon Jessica, Anderson V Elving, Sanguinetti Michael C, Leppert Mark F
Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA.
Brain. 2003 Dec;126(Pt 12):2726-37. doi: 10.1093/brain/awg286. Epub 2003 Oct 8.
Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant generalized epilepsy of the newborn infant. Seizures occur repeatedly in the first days of life and remit by approximately 4 months of age. Previously our laboratory cloned two novel potassium channel genes, KCNQ2 and KCNQ3, and showed that they are mutated in patients with BFNC. In this report, we characterize the breakpoints of a previously reported interstitial deletion in the KCNQ2 gene and show that only KCNQ2 is deleted. We identify 11 novel mutations in KCNQ2 and one novel mutation in the KCNQ3 potassium channel genes. In one family, the phenotype extends beyond neonatal seizures and includes rolandic seizures, and a subset of families has onset of seizures in infancy. In the Xenopus oocyte expression system, we characterize five KCNQ2 and one KCNQ3 disease-causing mutations. These mutations cause a variable loss of function, and selective effects on the biophysical properties of KCNQ2/KCNQ3 heteromultimeric channels. We report here the first dominant negative mutation in KCNQ2 that has a phenotype of neonatal seizures without permanent clinical CNS impairment.
良性家族性新生儿惊厥（BFNC）是一种罕见的常染色体显性遗传的新生儿全身性癫痫。惊厥在出生后的头几天反复出现，约在4个月大时缓解。此前我们实验室克隆了两个新的钾通道基因KCNQ2和KCNQ3，并发现它们在BFNC患者中发生了突变。在本报告中，我们对先前报道的KCNQ2基因间质性缺失的断点进行了表征，并表明只有KCNQ2被缺失。我们在KCNQ2基因中鉴定出11个新突变，在KCNQ3钾通道基因中鉴定出1个新突变。在一个家族中，表型超出了新生儿惊厥范围，还包括罗兰多癫痫发作，并且有一部分家族的癫痫发作始于婴儿期。在非洲爪蟾卵母细胞表达系统中，我们对5个KCNQ2和1个KCNQ3致病突变进行了表征。这些突变导致功能的可变丧失，以及对KCNQ2/KCNQ3异源多聚体通道生物物理特性的选择性影响。我们在此报告KCNQ2中首个显性负性突变，其表型为新生儿惊厥且无永久性临床中枢神经系统损害。
