L-type calcium channels and neuropsychiatric diseases: Insights into genetic risk variant-associated genomic regulation and impact on brain development.
L-type calcium channels and neuropsychiatric diseases: Insights into genetic risk variant-associated genomic regulation and impact on brain development.
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DOI：
10.1080/19336950.2023.2176984
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发表时间：
2023-12
期刊：
影响因子：
3.3
通讯作者：
Rajadhyaksha, Anjali M.
中科院分区：
文献类型：
--
作者：
Baker, Madelyn R.;Lee, Andrew D. S.;Rajadhyaksha, Anjali M.
最近的人类遗传学研究已经将CACNA1C和CACNA1D基因中的各种遗传变异与神经精神和神经发育障碍联系起来。这并不奇怪，因为多个实验室使用细胞和动物模型的工作已经确定，分别由CACNA1C和CACNA1D编码的Cav1.2和Cav1.3 L型钙通道（LTCC）在各种神经元过程中发挥关键作用，这些神经元过程对正常的大脑发育，连接和经验依赖性可塑性至关重要。在报道的多种遗传畸变中，全基因组关联研究（GWAS）已经确定了CACNA1C和CACNA1D中存在于内含子中的多个单核苷酸多态性（SNP），这与越来越多的文献一致，这些文献确定了与复杂疾病（包括神经精神疾病）相关的大量SNP存在于非编码区中。这些内含子SNP如何影响基因表达仍然是一个问题。在这里，我们回顾了最近的研究，这些研究开始揭示神经精神病学相关的非编码遗传变异如何通过基因组和染色质水平的调控影响基因表达。我们还回顾了最近的研究，这些研究揭示了通过LTCCs改变的钙信号如何影响一些神经元发育过程，如神经发生，神经元迁移和神经元分化。总之，所描述的基因组调控的变化和神经发育的中断提供了LTCC基因的遗传变异导致神经精神和神经发育障碍的可能机制。
Recent human genetic studies have linked a variety of genetic variants in the CACNA1C and CACNA1D genes to neuropsychiatric and neurodevelopmental disorders. This is not surprising given the work from multiple laboratories using cell and animal models that have established that Cav1.2 and Cav1.3 L-type calcium channels (LTCCs), encoded by CACNA1C and CACNA1D, respectively, play a key role in various neuronal processes that are essential for normal brain development, connectivity, and experience-dependent plasticity. Of the multiple genetic aberrations reported, genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) in CACNA1C and CACNA1D that are present within introns, in accordance with the growing body of literature establishing that large numbers of SNPs associated with complex diseases, including neuropsychiatric disorders, are present within non-coding regions. How these intronic SNPs affect gene expression has remained a question. Here, we review recent studies that are beginning to shed light on how neuropsychiatric-linked non-coding genetic variants can impact gene expression via regulation at the genomic and chromatin levels. We additionally review recent studies that are uncovering how altered calcium signaling through LTCCs impact some of the neuronal developmental processes, such as neurogenesis, neuron migration, and neuron differentiation. Together, the described changes in genomic regulation and disruptions in neurodevelopment provide possible mechanisms by which genetic variants of LTCC genes contribute to neuropsychiatric and neurodevelopmental disorders.
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