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.
- clinical genetics
- genetic screening/counselling
- neuromuscular disease
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Contributors PS and XC performed most experiments and analysed data and wrote the manuscript. YH, CY, LZ and SP took care of the patients and collected clinical information. QL performed all hearing tests for the family. CW and AQ performed the ABR test in mice. ZX designed the ABR test in mice. YH and WH performed the histological staining. MX and ON participated in the animal behavioural studies. WL performed the enzyme activity assay. YH designed the study and wrote the paper.
Funding This study was supported by the Guangdong Provincial Natural Science Foundation (#2019A1515011929), National Natural Science Foundation of China (#81771225), Guangdong Provincial Scientific and Technologic Progression Fund (#2016A020215182) to YH and 973 programmes (#2014CB943002) to ZX.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.