CNTNAP2 and NRXN1 Are Mutated in Autosomal-Recessive Pitt-Hopkins-like Mental Retardation and Determine the Level of a Common Synaptic Protein in Drosophila
CNTNAP2 and NRXN1 Are Mutated in Autosomal-Recessive Pitt-Hopkins-like Mental Retardation and Determine the Level of a Common Synaptic Protein in Drosophila
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DOI：
10.1016/j.ajhg.2009.10.004
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发表时间：
2009-11-13
影响因子：
9.8
通讯作者：
Rauch, Anita
中科院分区：
文献类型：
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作者：
Zweier, Christiane;de Jong, Eiko K.;Rauch, Anita
CNTNAP 2和NRXN 1（neurexin超家族的两个远亲成员）的杂合拷贝数变体和SNP已反复与广泛的神经精神障碍（如发育性语言障碍、自闭症谱系障碍、癫痫和精神分裂症）相关。我们现在通过分子核型分析和CNTNAP 2和NRXN 1的突变筛查，在4名患有严重精神发育迟滞（MR）和可变特征（如自闭症行为、癫痫和呼吸异常）的患者中鉴定了纯合和复合杂合缺失和突变，这些患者的表型与Pitt-Hopkins综合征重叠。在我们的179例患者的队列中，CNTNAP 2的隐性缺陷的频率至少为1%，似乎显着有助于严重MR。而NRXN 1的既定突触作用表明，突触缺陷有助于相关的神经精神疾病和严重MR，如本文所报道的，CNTNAP 2编码的蛋白CASPR 2的突触作用的证据迄今为止还缺乏。使用果蝇作为模型，我们现在表明，正如苍蝇Nrx-1所知，CASPR 2直系同源物Nrx-IV也可能定位于突触。任何一种蛋白的过表达都可以重组突触形态，并诱导活性区（神经递质释放的突触区域）密度增加。此外，Nrx-I和Nrx-IV都决定了突触前活性区蛋白bruchpilot的水平，表明Nrx-I和Nrx-IV突变条件下可能存在共同的分子机制。因此，我们提出，一个类似的共享突触机制有助于人类NRXN 1和CNTNAP 2缺陷导致的类似临床表型。
Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1, two distantly related members of the neurexin superfamily, have been repeatedly associated with a wide spectrum of neuropsychiatric disorders, such as developmental language disorders, autism spectrum disorders, epilepsy, and schizophrenia. We now identified homozygous and compound-heterozygous deletions and mutations via molecular karyotyping and mutational screening in CNTNAP2 and NRXN1 in four patients with severe mental retardation (MR) and variable features, such as autistic behavior, epilepsy, and breathing anomalies, phenotypically overlapping with Pitt-Hopkins syndrome. With a frequency of at least 1% in our cohort of 179 patients, recessive defects in CNTNAP2 appear to significantly contribute to severe MR. Whereas the established synaptic role of NRXN1 suggests that synaptic defects contribute to the associated neuropsychiatric disorders and to severe MR as reported here, evidence for a synaptic role of the CNTNAP2-encoded protein CASPR2 has so far been lacking. Using Drosophila as a model, we now show that, as known for fly Nrx-1, the CASPR2 ortholog Nrx-IV might also localize to synapses. Overexpression of either protein can reorganize synaptic morphology and induce increased density of active zones, the synaptic domains of neurotransmitter release. Moreover, both Nrx-I and Nrx-IV determine the level of the presynaptic active-zone protein bruchpilot, indicating a possible common molecular mechanism in Nrx-1 and Nrx-IV mutant conditions. We therefore propose that an analogous shared synaptic mechanism contributes to the similar clinical phenotypes resulting from defects in human NRXN1 and CNTNAP2.