首页|A human-specific cytotoxic neopeptide generated by the deafness gene Cingulin

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

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Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to or-gans.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 non-syndromic 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.

ProteinopathyAggregateNeopeptideCell deathCingulinHearing loss

Yuhang Huang、Linqing Zhang、Yuecen Sun、Qing Liu、Jie Chen、Xiaoyun Qian、Xia Gao、Guang-Jie Zhu、Guoqiang Wan

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MOE Key Laboratory of Model Animal for Disease Study,Department of Otolaryngology Head and Neck Surgery,Jiangsu Provincial Key Medical Discipline(Laboratory),The Affiliated Drum Tower Hospital of Medical School,Model Animal Research Center of Medical School,Nanjing University,Nanjing,Jiangsu 210061,China

Jiangsu Key Laboratory of Molecular Medicine and National Resource Center for Mutant Mice of China,Nanjing University,Nanjing,Jiangsu 210061,China

Research Institute of Otolaryngology,No.321 Zhongshan Road

Research Institute of Otolaryngology,No.321 Zhongshan Road,Nanjing,Jiangsu 210061,China

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2024

10.1016/j.jgg.2024.07.017

遗传学报
中国遗传学会 中国科学院遗传与发育生物学研究所

遗传学报

CSTPCD
影响因子：0.821
ISSN：1673-8527
年,卷(期)：2024.51(11)