南京大学万国强等研究人员合作发现，人类特异性细胞毒性新肽由耳聋基因Cingulin生成。相关论文于2024年8月5日在线发表在《遗传学报》上。

研究人员发现突变的Cingulin（CGN）蛋白形成不溶性聚集物，这些聚集物在细胞内积累并导致细胞死亡。在小鼠中表达突变的CGN蛋白会导致严重的毛细胞死亡和听力丧失，这与人类患者的听觉表型相似。有趣的是，移码突变生成的新肽中，人类特异性残基（V1112）对于突变人CGN的聚集和细胞毒性至关重要。

此外，热休克因子1 (HSF1) 的表达可以减少不溶性突变CGN聚集物的积累并拯救细胞死亡。总之，这些发现识别了突变特异性有毒多肽作为CGN耳聋突变的致病机制，并可以通过表达细胞伴侣反应调节因子HSF1进行靶向治疗。

研究人员表示，突变蛋白在细胞中的积累可以引发蛋白病并对器官造成功能损害。最近研究表明，CGN蛋白在维持内耳毛细胞的角质板形态方面发挥作用，而CGN中的移码突变会导致常染色体显性非综合征听力丧失。

附：英文原文

Title: A human-specific cytotoxic neopeptide generated by the deafness gene Cingulin

Author: Xia Gao a c, Guang-Jie Zhu a c, Guoqiang Wan a b c

Issue&Volume: 2024/08/05

Abstract: Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to organs. Recently, the Cingulin (CGN) protein has been shown to maintain the morphology of cuticular plates of inner ear hair cells and a frameshift mutation in CGN causes autosomal dominant nonsyndromic hearing loss. Here, we find that the mutant CGN proteins form insoluble aggregates which accumulate intracellularly and lead to cell death. Expression of the mutant CGN in the inner ear results in severe hair cell death and hearing loss in mice, resembling the auditory phenotype in human patients. Interestingly, a human-specific residue (V1112) in the neopeptide generated by the frameshift mutation is critical for the aggregation and cytotoxicity of the mutant human CGN. Moreover, the expression of heat shock factor 1 (HSF1) decreases the accumulation of insoluble mutant CGN aggregates and rescues cell death. In summary, these findings identify mutant-specific toxic polypeptides as a disease-causing mechanism of the deafness mutation in CGN, which can be targeted by the expression of the cell chaperone response regulator HSF1.

DOI: 10.1016/j.jgg.2024.07.017

Source: https://www.sciencedirect.com/science/article/abs/pii/S1673852724001954