Frameshift mutation of Timm8a1 gene in mouse leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment.

Published on Sep 1, 2021in Journal of Medical Genetics4.943
· DOI :10.1136/JMEDGENET-2020-106925
Pingping Song4
Estimated H-index: 4
(Southern Medical University),
Yuqing Guan2
Estimated H-index: 2
(Southern Medical University)
+ 14 AuthorsYafang Hu12
Estimated H-index: 12
(Southern Medical University)
Sources
Abstract
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, 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.
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BACKGROUND: The rare, X-linked neurodegenerative disorder, Mohr-Tranebjaerg syndrome (also called deafness-dystonia-optic neuronopathy [DDON] syndrome), is caused by mutations in the TIMM8A gene. DDON syndrome is characterized by dystonia, early-onset deafness, and various other neurological manifestations. The TIMM8A gene product localizes to the intermembrane space in mitochondria where it functions in the import of nuclear-encoded proteins into the mitochondrial inner membrane. Frameshifts or...
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Deafness-Dystonia-Optic Neuropathy (DDON) Syndrome is a rare X-linked progressive neurodegenerative disorder resulting from mutations in the TIMM8A gene encoding for the deafness dystonia protein 1 (DDP1). Despite important progress in identifying and characterizing novel mutations in this gene, little is known about the underlying pathomechanisms. Deficiencies in the biogenesis of hTim23 and consecutive alterations in biogenesis of inner membrane and matrix proteins have been proposed to serve ...
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