Mutation of a potassium channel-related gene in progressive myoclonic epilepsy
Mutation of a potassium channel-related gene in progressive myoclonic epilepsy
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DOI：
10.1002/ana.21121
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发表时间：
2007-06-01
影响因子：
11.2
通讯作者：
Abramowicz, Marc J.
中科院分区：
文献类型：
--
作者：
Van Bogaert, Patrick;Azizieh, Regis;Abramowicz, Marc J.
目的：研究一个具有常染色体隐性遗传的进行性肌阵挛性癫痫（PME）摩洛哥大近亲家族，描述其表型并确定致病基因。方法：我们记录疾病的临床过程和对药物治疗的反应，同时仔细排除进行性肌阵挛性癫痫的已知原因。然后，我们使用微卫星标记和单核苷酸多态性微阵列（11K GeneChip）通过纯合子定位将该疾病联系起来，并研究了关键连锁区域的候选基因。结果：癫痫开始于正常初始发育后的16 - 24个月。癫痫发作为多局灶性肌阵挛，运动加重，2例患者出现全身性强直阵挛发作。脑电图显示缓慢的心律失常，多灶性和偶尔广泛性癫痫样放电，光敏性。脑磁共振成像正常。所有的病人都精神错乱。其中2例为难治性癫痫，病程严重。第三例患者癫痫发作得到控制，病程较轻。连锁分析在7q11.2上发现了一个新的位点，D7S663位点的最大多点对数概率为4.0。在关键连锁区，我们发现含有7基因的钾通道四聚域（KCTD7）的外显子2发生C到T突变。突变影响了预测蛋白的高度保守部分，将精氨酸密码子改变为停止密码子（R99X）。解释：我们的患者在进行性肌阵挛性癫痫中表现出的神经变性与癫痫的难治性相似。该疾病是作为常染色体隐性性状传播的，与7q11.2的新位点相关，在那里我们发现了KCTD7的突变。
Objective: We investigated a large consanguineous Moroccan family with progressive myoclonic epilepsy (PME) consistent with autosomal recessive inheritance, to describe the phenotype and identify the causal gene.Methods: We recorded the clinical course of the disease and the response to drug therapy, whereas carefully excluding known causes of progressive myoclonic epilepsy. We then linked the disease by homozygosicy mapping using microsatellite markers and single nucleotide polymorphism microarrays (11K GeneChip), and studied candidate genes in the critical linkage region.Results: Epilepsy started between 16 and 24 months of age after normal initial development. Seizures were multifocal myoclonus aggravated by movements, and generalized tonic-clonic seizures were experienced by two patients. Electroencephalogram showed slow dysrhythmia, multifocal and occasionally generalized epileptiform discharges, and photosensitivity. Brain magnetic resonance images were normal. All patients were demented. Two had refractory epilepsy and a severe course. Seizures were controlled in the third patient, whose disease course was less severe. Linkage analyses identified a new locus on 7q11.2, with a maximum multipoint logarithm of odds of 4.0 at D7S663. In the critical linkage region, we found a C to T mutation in exon 2 of the potassium channel tetramerization domain containing 7 gene (KCTD7). The mutation affected a highly conserved segment of the predicted protein, changing an arginine codon into a stop codon (R99X).Interpretation: Neurodegeneration in progressive myoclonic epilepsy presented by our patients paralleled the refractoriness of epilepsy. The disease was transmitted as an autosomal recessive trait linked to a novel locus at 7q11.2, where we identified a mutation in KCTD7.