Department of Human and Molecular Genetics, Virginia Commonwealth University, 1101 East Marshall Street, Richmond, VA, 23298-0033, USA.
Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA.
J Psychiatr Res. 2019 Apr;111:8-15. doi: 10.1016/j.jpsychires.2019.01.007. Epub 2019 Jan 10.
CMYA5 is a candidate gene for schizophrenia because of the genetic association of variant rs10043986 (C > T) to this severe mental disorder. Studies of CMYA5 and its gene product, myospryn, in the brain and neuronal cells have not been previously reported. The SNP rs10043986 changes the 4,063rd amino acid from Pro to Leu, which is likely to alter protein function. To understand its potential role in the brain, we examined the neuronal expression of myospryn and its binding partner, desmin, an intermediate filament (IF) protein, and investigated how the two alleles of myospryn affect its binding to desmin. Myospryn and desmin are shown to be expressed in the brain and myospryn is shown to localize to the cytoplasm and nucleus of myoblast, neuroblastoma, and glioblastoma cell lines. Peripherin and vimentin, known brain IF proteins, have high protein similarity to desmin but were found not to interact with myospryn using yeast two-hybrid (Y2H). Using a quantitative Y2H assay and surface plasmon resonance, the T allele (Leu) of rs10043986 was found to have stronger binding to desmin than the C allele (Pro). Based on findings described in this report, we hypothesize that the interaction between myospryn to IF provides structural support and efficient rearrangement of the cytoskeleton network during early neuritogenesis.
CMYA5 是精神分裂症的候选基因，因为其变体 rs10043986（C>T）与这种严重的精神障碍存在遗传关联。此前尚未有关于 CMYA5 及其基因产物肌联蛋白在大脑和神经元细胞中的研究报道。SNP rs10043986 将第 4063 位氨基酸由脯氨酸突变为亮氨酸，这很可能改变蛋白质的功能。为了了解其在大脑中的潜在作用，我们研究了肌联蛋白及其结合伴侣中间丝蛋白 desmin 的神经元表达情况，并研究了肌联蛋白的两种等位基因如何影响其与 desmin 的结合。结果表明，肌联蛋白和 desmin 在大脑中表达，肌联蛋白定位于成肌细胞、神经母细胞瘤和神经胶质瘤细胞系的细胞质和细胞核。已知的脑中间丝蛋白 peripherin 和 vimentin 与 desmin 具有很高的蛋白相似性，但使用酵母双杂交（Y2H）实验并未发现它们与肌联蛋白相互作用。通过定量 Y2H 测定和表面等离子体共振实验，发现 rs10043986 的 T 等位基因（亮氨酸）与 desmin 的结合比 C 等位基因（脯氨酸）更强。基于本报告中描述的发现，我们假设肌联蛋白与 IF 之间的相互作用为早期神经突发生过程中提供了细胞骨架网络的结构支撑和有效的重排。
