Heilstedt H A, Burgess D L, Anderson A E, Chedrawi A, Tharp B, Lee O, Kashork C D, Starkey D E, Wu Y Q, Noebels J L, Shaffer L G, Shapira S K
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Epilepsia. 2001 Sep;42(9):1103-11. doi: 10.1046/j.1528-1157.2001.08801.x.
Clinical features associated with chromosome 1p36 deletion include characteristic craniofacial abnormalities, mental retardation, and epilepsy. The presence and severity of specific phenotypic features are likely to be correlated with loss of a distinct complement of genes in each patient. We hypothesize that hemizygous deletion of one, or a few, critical gene(s) controlling neuronal excitability is associated with the epilepsy phenotype. Because ion channels are important determinants of seizure susceptibility and the voltage-gated K(+) channel beta-subunit gene, KCNAB2, has been localized to 1p36, we propose that deletion of this gene may be associated with the epilepsy phenotype.
Twenty-four patients were evaluated by fluorescence in situ hybridization with a probe containing KCNAB2. Clinical details were obtained by neurologic examination and EEG.
Nine patients are deleted for the KCNAB2 locus, and eight (89%) of these have epilepsy or epileptiform activity on EEG. The majority of patients have a severe seizure phenotype, including infantile spasms. In contrast, of those not deleted for KCNAB2, only 27% have chronic seizures, and none had infantile spasms.
Lack of the beta subunit would be predicted to reduce K(+) channel-mediated membrane repolarization and increase neuronal excitability, suggesting a possible relation between loss of this gene and the development of seizures. Because some patients with seizures were not deleted for KCNAB2, there may be additional genes within 1p36 that contribute to epilepsy in this syndrome. Hemizygosity of this gene in a majority of monosomy 1p36 syndrome patients with epilepsy suggests that haploinsufficiency for KCNAB2 is a significant risk factor for epilepsy.
与1p36染色体缺失相关的临床特征包括典型的颅面畸形、智力迟钝和癫痫。特定表型特征的存在和严重程度可能与每位患者不同基因互补体的缺失有关。我们假设一个或几个控制神经元兴奋性的关键基因的半合子缺失与癫痫表型相关。由于离子通道是癫痫易感性的重要决定因素，且电压门控钾通道β亚基基因KCNAB2已定位到1p36，我们提出该基因的缺失可能与癫痫表型有关。
采用含KCNAB2的探针通过荧光原位杂交对24例患者进行评估。通过神经学检查和脑电图获取临床细节。
9例患者的KCNAB2基因座缺失，其中8例（89%）脑电图显示有癫痫或癫痫样活动。大多数患者有严重的癫痫表型，包括婴儿痉挛症。相比之下，未缺失KCNAB2的患者中，只有27%有慢性癫痫发作，且无婴儿痉挛症患者。
预计β亚基的缺失会减少钾通道介导的膜复极化并增加神经元兴奋性，提示该基因缺失与癫痫发作的发生可能存在关联。由于一些癫痫患者未缺失KCNAB2，1p36区域内可能还有其他基因导致该综合征中的癫痫。大多数患有癫痫的1p36单体综合征患者中该基因的半合子状态表明，KCNAB2单倍剂量不足是癫痫的一个重要危险因素。
