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Background: Deafness-dystonia-optic neuronopathy (DDON) syndrome is a progressive X-linked recessive disorder characterised by deafness, dystonia, ataxia and reduced visual acuity. The causative gene deafness/dystonia protein 1 ( DDP1 ) / translocase of the inner membrane 8A ( TIMM8A ) encodes a mitochondrial intermembrane space chaperon. The molecular mechanism of DDON remains unclear, and detailed information on animal models has not been reported yet., Methods and Results: We characterized a family with DDON syndrome, in which the affected members carried a novel hemizygous variation in the DDP1 gene (NM_004085.3, c.82C>T, p.Q28X). We then generated a mouse line with the hemizygous mutation (p.I23fs49X) in the Timm8a1 gene using the clustered regularly interspaced short palindromic repeats /Cas9 technology. The deficient DDP1 protein was confirmed by western blot assay. Electron microscopic analysis of brain samples from the mutant mice indicated abnormal mitochondrial structure in several brain areas. However, Timm8a1 I23fs49X/y mutation did not affect the import of mitochondria inner member protein Tim23 and outer member protein Tom40 as well as the biogenesis of the proteins in the mitochondrial oxidative phosphorylation system and the manganese superoxide dismutase (MnSOD / SOD-2). The male mice with Timm8a1 I23fs49X/y mutant exhibited less weight gain, hearing impairment and cognitive deficit., Conclusion: Our study suggests that frameshift mutation of the Timm8a1 gene in mice leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment. Taken together, we have successfully generated a mouse model bearing loss-of-function mutation in Timm8a1 ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)