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BackgroundDeafness-dystonia-optic neuronopathy (DDON) syndrome, a condition that predominantly affects males, is caused by mutations in translocase of mitochondrial inner membrane 8A (TIMM8A)/deafness dystonia protein 1 (DDP1) gene and characterized by progressive deafness coupled with other neurological abnormalities. In a previous study, we demonstrated the phenotype of male mice carrying the hemizygous mutation of Timm8a1-I23fs49X. In a follow-up to that study, this study aimed to observe the behavioral changes in the female mutant (MUT) mice with homologous mutation of Timm8a1 and to elucidate the underlying mechanism for the behavioral changes.Materials and methodsHistological analysis, transmission electron microscopy (EM), Western blotting, hearing measurement by auditory brainstem response (ABR), and behavioral observation were compared between the MUT mice and wild-type (WT) littermates.ResultsThe weight of the female MUT mice was less than that of the WT mice. Among MUT mice, both male and female mice showed hearing impairment, anxiety-like behavior by the elevated plus maze test, and cognitive deficit by the Morris water maze test. Furthermore, the female MUT mice exhibited coordination problems in the balance beam test. Although the general neuronal loss was not found in the hippocampus of the MUT genotype, EM assessment indicated that the mitochondrial size showing as aspect ratio and form factor in the hippocampus of the MUT strain was significantly reduced compared to that in the WT genotype. More importantly, this phenomenon was correlated with the upregulation of translation of mitochondrial fission process protein 1(Mtfp1)/mitochondrial 18 kDa protein (Mtp18), a key fission factor that is a positive regulator of mitochondrial fission and mitochondrial size. Interestingly, significant reductions in the size of the uterus and ovaries were noted in the female MUT mice, which contributed to significantly lower fertility in the MUT mice.ConclusionTogether, a homologous mutation in the Timm8a1 gene caused the hearing impairment and psychiatric behavioral changes in the MUT mice; the latter phenotype might be related to a reduction in mitochondrial size regulated by MTP18.

The African grasscutter (AGC) (Thryonomys swinderianus) is the second largest rodent in sub‐Saharan Africa. It is bred for its organoleptic and culinary properties but also serves as a research model. The aim of this study was to investigate the relationship between age‐related changes in brain weight, brain volume, and spatial and nonspatial memory performance in the AGC. A total of forty‐two (42) captive‐derived AGCs were divided into seven age groups: 6 neonates (6 days), 6 juveniles (1 month), 6 pubertals (3 months), 6 subadults (8 months), 6 young adults (2 years), 6 middle adults (4 years), and 6 old adults (5 years). The subjects were given a series of tests to assess their spatial memory (location test) and their nonspatial memory (object recognition test). Brain samples were then collected using basic neuroanatomical techniques. The weight and volume of the brain samples were determined and their encephalization quotient (EQ) was also calculated. The results showed that spatial and nonspatial memory in AGC develops into adulthood and then declines with age. Mean brain weight increased from neonates to mid‐adulthood (5.20 ± 0.31 g–11.76 ± 0.23 g) and decreased in older AGC (11.75 ± 0.22 g). In contrast, the mean weight of the olfactory bulb (OB) increased from neonates to young adults (0.28 ± 0.02 g–0.80 ± 0.03 g) and the cerebellum increased from neonates to older (0.59 ± 0 0.01 g–1.86 ± 0.06 g). Finally, the EQ decreased with age (0.73 ± 0.05–0.29 ± 0.01). Mean brain volume increased with age from neonates to young adult (5 mL–11.25 mL). Conversely, the mean volume of the OB and cerebellum increases from neonates to older age (0.33 ± 0.03 mL–0.95 ± 0.04 mL). This study shows that spatial and nonspatial memory declines during the aging process in AGC. Neonates and juveniles have higher cognitive abilities than adults and older AGC. The weight of the brain, OB, and cerebellum increases from neonates to adult and decreases slightly from middle to old adults. However, the volume of the OB and cerebellum increases with age. [ABSTRACT FROM AUTHOR]

Background Deafness-dystoniaoptic 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, Timm8a1I23fs49X/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 Timm8a1I23fs49X/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. [ABSTRACT FROM AUTHOR]

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.)