Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene.
Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene.
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DOI：
10.1136/jmedgenet-2012-100859
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发表时间：
2012-06
影响因子：
4
通讯作者：
Lehesjoki AE
中科院分区：
文献类型：
--
作者：
Kousi M;Anttila V;Schulz A;Calafato S;Jakkula E;Riesch E;Myllykangas L;Kalimo H;Topçu M;Gökben S;Alehan F;Lemke JR;Alber M;Palotie A;Kopra O;Lehesjoki AE
进行性肌阵挛性癫痫（PMEs）包括一组临床和遗传异质性疾病，其特征在于肌阵挛、癫痫和神经功能恶化。我们的目的是确定潜在的基因在儿童期发病的PME患者未知的分子遗传背景。纯合性作图应用于18名土耳其患者的全基因组SNP数据。含钾通道四聚化结构域7（KCTD 7）基因，以前与PME在一个单一的近交系，进行了筛选突变。在细胞培养物和小鼠脑组织中评估KCTD 7的时空表达。8/18例患者的重叠纯合性将7q11.21上的1.5Mb片段定义为主要候选基因座。位置候选基因KCTD 7的筛选显示在8例中的2例纯合错义突变。在另外132名PME患者中筛查KCTD 7，发现5个家族中有4个额外的突变（2个错义突变，1个框内缺失突变和1个移码突变）。8例患者出现肌阵挛和癫痫，1例出现共济失调，平均发病年龄为19个月。在发病后两年内，精神和运动技能逐渐丧失，导致严重的痴呆和运动障碍。KCTD 7显示出胞浆定位和主要的神经元表达，在整个大脑中广泛表达。三种携带错义突变的多肽均不影响KCTD 7的亚细胞分布。我们的数据证实了KCTD 7缺陷在PME中的因果关系，并意味着在2岁左右发病的PME患者中应考虑KCTD 7突变筛查，然后快速精神和运动恶化。
The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterized by myoclonus, epilepsy, and neurological deterioration. We aimed to identify the underlying gene(s) in childhood-onset PME patients with unknown molecular genetic background. Homozygosity mapping was applied on genome-wide SNP data of 18 Turkish patients. The potassium channel tetramerization domain-containing 7 (KCTD7) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue. Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within two years after onset progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localization and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7. Our data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.
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影响因子：
11.2
作者：
Van Bogaert, Patrick;Azizieh, Regis;Abramowicz, Marc J.
通讯作者：
Abramowicz, Marc J.
影响因子：
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作者：
Argenti, B;Gallo, R;Gulino, A
通讯作者：
Gulino, A
影响因子：
3.9
作者：
Kousi, Maria;Lehesjoki, Anna-Elina;Mole, Sara E.
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Mole, Sara E.
影响因子：
4.8
作者：
Bartoi, Tudor;Rigbolt, Kristoffer T. G.;Kornau, Hans-Christian
通讯作者：
Kornau, Hans-Christian
影响因子：
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作者：
Noskova, Lenka;Stranecky, Viktor;Kmoch, Stanislav
通讯作者：
Kmoch, Stanislav