Potential involvement of DSCAML1 mutations in neurodevelopmental disorders
Potential involvement of DSCAML1 mutations in neurodevelopmental disorders
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DOI：
10.1111/gtc.12831
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发表时间：
2021-02-18
期刊：
影响因子：
2.1
通讯作者：
Hoshino, Mikio
中科院分区：
文献类型：
--
作者：
Ogata, Shigehiro;Hashizume, Koichi;Hoshino, Mikio
神经发育障碍(NDDS)的分子机制尚不清楚。我们以前发现唐氏综合征细胞黏附分子样1(Dscaml1)是Ihara癫痫大鼠(Ihara癫痫大鼠)的负责基因，Ihara癫痫大鼠是人类NDDS合并癫痫的大鼠模型。然而，人类中NDDS和DSCAML1之间的关系仍然难以捉摸。在这项研究中，我们筛选了自闭症谱系障碍(ASD)、智力残疾(ID)/发育障碍(DD)和精神分裂症数据库中人类DSCAML1的基因组突变。然后，我们进行了计算机分析，以估计突变的DSCAML1蛋白的潜在损害，并选择了三个具有代表性的突变(DSCAML1(C729R)、DSCAML1(R1685*)和DSCAML1(K2108Nfs*37))，它们分别在第七个Ig结构域、胞内区和C-末端PDZ结合基序中缺少半胱氨酸残基。在细胞系的过表达实验中，DSCAML1(C729R)失去了成熟的N-糖基化，而DSCAML1(K2108Nfs*37)则通过蛋白酶体依赖的蛋白质降解而异常降解。此外，在原代海马神经元中，野生型DSCAML1与所有突变蛋白一起失去了调节突触数量的能力。这些结果有助于理解DSCAML1蛋白中这些结构域的作用，并进一步表明这些突变会导致功能变化，尽管机制不同，但可能会影响NDDS的病理生理。
The molecular mechanisms underlying neurodevelopmental disorders (NDDs) remain unclear. We previously identified Down syndrome cell adhesion molecule like 1 (Dscaml1) as a responsible gene for Ihara epileptic rat (IER), a rat model for human NDDs with epilepsy. However, the relationship between NDDs and DSCAML1 in humans is still elusive. In this study, we screened databases of autism spectrum disorders (ASD), intellectual disability (ID)/developmental disorders (DD) and schizophrenia for genomic mutations in human DSCAML1. We then performed in silico analyses to estimate the potential damage to the mutated DSCAML1 proteins and chose three representative mutations (DSCAML1(C729R), DSCAML1(R1685*) and DSCAML1(K2108Nfs*37)), which lacked a cysteine residue in the seventh Ig domain, the intracellular region and the C-terminal PDZ-binding motif, respectively. In overexpression experiments in a cell line, DSCAML1(C729R) lost its mature N-glycosylation, whereas DSCAML1(K2108Nfs*37) was abnormally degraded via proteasome-dependent protein degradation. Furthermore, in primary hippocampal neurons, the ability of the wild-type DSCAML1 to regulate the number of synapses was lost with all mutant proteins. These results provide insight into understanding the roles of the domains in the DSCAML1 protein and further suggest that these mutations cause functional changes, albeit through different mechanisms, that likely affect the pathophysiology of NDDs.