Alterations in CDH15 and KIRREL3 in Patients with Mild to Severe Intellectual Disability
Alterations in CDH15 and KIRREL3 in Patients with Mild to Severe Intellectual Disability
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DOI：
10.1016/j.ajhg.2008.10.020
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发表时间：
2008-12-12
影响因子：
9.8
通讯作者：
Srivastava, Anand K.
中科院分区：
文献类型：
--
作者：
Bhalla, Kavita;Luo, Yue;Srivastava, Anand K.
细胞粘附分子在大脑发育中起着关键作用，以及维持突触结构，功能和可塑性。在这里，我们发现了两个基因的破坏编码推定的细胞粘附分子，CDH 15（钙粘蛋白超家族）和KIRP 13（免疫球蛋白超家族），染色体易位t（11;16）在女性患者智力残疾（ID）。我们筛选了这两个基因的编码区在一个队列的患者ID和控制，并确定了4个非同义的CDH 15变异体和3个非同义的KIRRY 3变异体，出现罕见的和独特的ID。这些变化改变了高度保守的残基，并没有在600多个无关的ID患者和800个控制个人。此外，体内表达研究表明，三个CDH 15的变化，不利地改变其能力，介导细胞-细胞粘附。我们还表明，在神经元细胞中，人类KIRR 13共定位和相互作用的突触支架蛋白，CASK，最近牵连在X-连锁脑畸形和ID。两者合计，我们的数据表明，在CDH 15和KIRR 13的改变，单独或与其他因素相结合，可以发挥作用，在某些患者的ID表型表达。
Cell-adhesion molecules play critical roles in brain development, as well as maintaining synaptic structure, function, and plasticity. Here we have found the disruption of two genes encoding putative cell-adhesion molecules, CDH15 (cadherin superfamily) and KIRREL3 (immunoglobulin superfamily), by a chromosomal translocation t(11;16) in a female patient with intellectual disability (ID). We screened coding regions of these two genes in a cohort of patients with ID and controls and identified four nonsynonymous CDH15 variants and three nonsynonymous KIRREL3 variants that appear rare and unique to ID. These variations altered highly conserved residues and were absent in more than 600 unrelated patients with ID and 800 control individuals. Furthermore, in vivo expression studies showed that three of the CDH15 variations adversely altered its ability to mediate cell-cell adhesion. We also show that in neuronal cells, human KIRREL3 colocalizes and interacts with the synaptic scaffolding protein, CASK, recently implicated in X-linked brain malformation and ID. Taken together, our data suggest that alterations in CDH15 and KIRREL3, either alone or in combination with other factors, could play a role in phenotypic expression of ID in some patients.