Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.
Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females.
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DOI：
10.1371/journal.pgen.1000381
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发表时间：
2009-02
期刊：
影响因子：
4.5
通讯作者：
LeGuern, Eric
中科院分区：
文献类型：
--
作者：
Depienne, Christel;Bouteiller, Delphine;Keren, Boris;Cheuret, Emmanuel;Poirier, Karine;Trouillard, Oriane;Benyahia, Baya;Quelin, Chloe;Carpentier, Wassila;Julia, Sophie;Afenjar, Alexandra;Gautier, Agnes;Rivier, Francois;Meyer, Sophie;Berquin, Patrick;Helias, Marie;Py, Isabelle;Rivera, Serge;Bahi-Buisson, Nadia;Gourfinkel-An, Isabelle;Cazeneuve, Cecile;Ruberg, Merle;Brice, Alexis;Nabbout, Rima;LeGuern, Eric
Dravet综合征（DS）是一种主要由SCN1A基因从头突变引起的遗传性癫痫性脑病。自2003年以来，我们对大量DS患者进行了分子分析，其中27%的患者SCN1A突变或重排呈阴性。为了在scn1a阴性患者中发现导致该疾病的新基因，我们使用Illumina高密度SNP微阵列筛选了41个先证者进行微重排。在一名男性患者中发现了包含PCDH19基因的染色体Xq22.1上的半合子缺失。为了证实PCDH19与dravet样综合征有关，我们对另外73例scn1a阴性患者的PCDH19编码区进行了测序。在11例无亲缘关系的女性患者中发现了9个不同的点突变（4个错义突变和5个截断突变）。此外，我们证明了我们的男性患者的成纤维细胞是镶嵌的PCDH19缺失。PCDH19和SCN1A突变患者具有非常相似的临床特征，包括早期发热和无热性癫痫发作、丛集性癫痫发作、发育和语言延迟、行为障碍以及认知衰退。然而，在患者的进化过程中存在着细微但持续的差异，包括PCDH19突变患者的多态癫痫发作（特别是罕见的肌阵挛性抽搐和非典型缺失）较少。这些结果表明PCDH19在癫痫性脑病中起主要作用，其临床谱与DS重叠。这种疾病主要影响女性。一个受影响的花叶雄性的鉴定有力地支持了细胞干扰是致病机制的假设。儿童与认知障碍相关的严重癫痫是多种多样的，大多数受影响的患者是零星病例。因此，确定哪些癫痫是由遗传决定的是一个挑战，因为它们的散发状态不允许使用经典的遗传方法。我们已经使用微阵列，这是一种新的技术工具来研究一个人的整个基因组，在41名患有临床特征明显的严重婴儿癫痫疾病（称为德拉韦综合征）的患者中寻找小的基因组异常并识别新的基因。我们已经确定了PCDH19，这是X染色体上的一个新基因，最近在一种被称为女性有限癫痫和认知障碍的家族性癫痫综合征中发现。该基因在74例临床特征与Dravet综合征相符的患者中的12例中发生突变。其中11例为女性。PCDH19缺乏的单身男性皮肤呈镶嵌状；也就是说，他的一些细胞表达PCDH19，而另一些则不表达。这一发现表明，一种新的致病机制——细胞干扰——与一种不寻常的x连锁遗传模式有关，在这种模式下，女性比男性更容易受到影响。
Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism. Severe epilepsies associated with cognitive impairment in children are multifarious and most affected patients are sporadic cases. Thus, there is a challenge to identify which of these epilepsies are genetically determined, since their sporadic status excludes the use of classical genetic approaches. We have used microarrays, which are new technological tools to investigate the whole genome of an individual, to search for small genomic abnormalities and identify novel genes in 41 patients with a clinically well-characterized severe infantile epileptic disorder called Dravet syndrome. We have identified PCDH19, a new gene on chromosome X, which was recently found in a familial epileptic syndrome known as female-limited epilepsy and cognitive impairment. This gene was mutated in 12 out of 74 patients with clinical features compatible with Dravet syndrome. Eleven of these patients were females. The single male with a PCDH19 deficiency was mosaic in his skin; i.e., some of his cells express PCDH19 and others do not. This finding suggests that a new pathogenic mechanism—cellular interference—is associated with an unusual X-linked mode of inheritance in which females are more frequently affected than males.
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