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首页> 外文期刊>Molecular syndromology >Intragenic CNTNAP2 Deletions: A Bridge Too Far?
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Intragenic CNTNAP2 Deletions: A Bridge Too Far?

机译：基因内CNTNAP2缺失：桥梁太远了？

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Intragenic deletions of the contactin-associated protein-like 2 gene (CNTNAP2) have been found in patients with Gilles de la Tourette syndrome, intellectual disability (ID), obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, stuttering, and attention deficit hyperactivity disorder. A variety of molecular mechanisms, such as loss of transcription factor binding sites and perturbation of penetrance and expressivity, have been proposed to account for the phenotypic variability resulting from CNTNAP2 mutations. Deletions of both CNTNAP2 alleles produced truncated proteins lacking the transmembrane or some of the extracellular domains, or no protein at all. This observation can be extended to heterozygous intragenic deletions by assuming that such deletion-containing alleles lead to expression of a Caspr2 protein lacking one or several extracellular domains. Such altered forms of Capr2 proteins will lack the ability to bridge the intercellular space between neurons by binding to partners, such as CNTN1, CNTN2, DLG1, and DLG4. This presumed effect of intragenic deletions of CNTNAP2, and possibly other genes involved in connecting neuronal cells, represents a molecular basis for the postulated neuronal hypoconnectivity in autism and probably other neurodevelopmental disorders, including epilepsy, ID, language impairments and schizophrenia. Thus, CNTNAP2 may represent a paradigmatic case of a gene functioning as a node in a genetic and cellular network governing brain development and acquisition of higher cognitive functions.
机译：已经发现吉尔斯·德·图雷特综合征，智力残疾（ID），强迫症，皮质发育不良-局灶性癫痫综合征，自闭症，精神分裂症，皮特-霍普金斯综合征，口吃和注意力缺陷多动障碍。已经提出了多种分子机制，例如转录因子结合位点的丧失以及渗透性和表达能力的扰动，来解释由CNTNAP2突变引起的表型变异性。两个CNTNAP2等位基因的缺失产生了截短的蛋白，该蛋白缺少跨膜或某些胞外域，或者根本没有蛋白。通过假定这种含有缺失的等位基因导致表达缺少一个或几个胞外域的Caspr2蛋白，可以将该观察扩展到杂合的基因内缺失。这种改变形式的Capr2蛋白将缺乏通过与伴侣（例如CNTN1，CNTN2，DLG1和DLG4）结合而桥接神经元之间的细胞间空间的能力。 CNTNAP2的基因内缺失的这种推测作用以及可能与连接神经元细胞有关的其他基因的这种作用，代表了自闭症和其他可能的神经发育障碍（包括癫痫症，ID，语言障碍和精神分裂症）中假定的神经元连通性低下的分子基础。因此，CNTNAP2可能代表基因的一个典型案例，该基因起着控制大脑发育和获得更高认知功能的遗传和细胞网络中的节点的作用。

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