Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy

Wang, Hongyang; Wang, Li; Yang, Ju Dong; Yin, Linwei; Lan, Lan; Li, Jin; Zhang, Qiujing; Wang, Dayong; Guan, Jing

doi:10.1186/s12881-018-0741-3

Cited by 14 publications

(22 citation statements)

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“…More recently, loss of Tim8a in neurons was shown to cause defects in Complex IV assembly, priming these cells for apoptotic vulnerability (Kang et al, 2019). Most of the mutations associated with DDON syndrome are frameshifts or premature stops, and there are a few missense mutations reported, including two in the first codon of the gene (Aguirre et al, 2006;Binder et al, 2003;Blesa et al, 2007;Hofmann et al, 2002;Penamora-Destriza et al, 2015;Ujike, Tanabe, Takehisa, Hayabara, & Kuroda, 2001;Wang et al, 2019). Whether these first codon mutations result in the utilization of an alternate start site, or whether they result in the complete loss of protein noted in other DDON syndrome patients, is not known.…”

Section: Of 7 |mentioning

confidence: 99%

Functional analysis of a novel mutation in the TIMM8A gene that causes deafness‐dystonia‐optic neuronopathy syndrome

Neighbors

Moss

Holloway

et al. 2020

Molec Gen & Gen Med

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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 premature stops represent the majority of mutations in TIMM8A that cause DDON syndrome. However, missense mutations have also been reported that result in loss of the TIMM8A gene product. Methods We report a novel TIMM8A variant in a patient with DDON syndrome that alters the initiation codon and employed functional analyses to determine the significance of the variant and its impact on mitochondrial morphology. Results The novel base change in the TIMM8A gene (c.1A>T, p.Met1Leu) results in no detectable protein and a reduction in TIMM8A transcript abundance. We observed a commensurate decrease in the steady‐state level of the Tim13 protein (the binding partner of Tim8a) but no decrease in TIMM13 transcripts. Patient fibroblasts exhibited elongation and/or increased fusion of mitochondria, consistent with prior reports. Conclusion This case expands the spectrum of mutations that cause DDON syndrome and demonstrates effects on mitochondrial morphology that are consistent with prior reports.

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Section: Of 7 |mentioning

confidence: 99%

Functional analysis of a novel mutation in the TIMM8A gene that causes deafness‐dystonia‐optic neuronopathy syndrome

Neighbors

Moss

Holloway

et al. 2020

Molec Gen & Gen Med

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“…From a clinical standpoint, early detection of patients with pathogenic variants in TIMM8A is important to guide parents and optimize patient treatment. It must be expected that new cases with congenital or early onset hearing impairment of the postsynaptic auditory neuropathy type, due to TIMM8A pathogenic variants, may be genetically diagnosed before they present with visual and neurological symptoms 9 .…”

Section: Discussionmentioning

confidence: 99%

“…The TIMM8A gene is relatively small, consisting of two exons encoding a 97 amino acid protein, which functions as a translocase of the inner mitochondrial membrane 4 . A list of variants in TIMM8A have been described, including missense, nonsense, splice site variants and small insertions/deletions (indels) as well as partial and whole gene deletions 3 , 5 – 9 . Furthermore, contiguous gene deletions including TIMM8A account for a large proportion of the variants reported 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Deletions causing Mohr-Tranebjærg syndrome by including partial or whole gene deletion of TIMM8A have been published previous in about 20 patients/families, but only few describing the deletions down to the nucleotide level 5 , 9 – 11 . Arai et al (2011) analyzed the genomic breakpoint in three XLA-MTS patients using methods such as array-CGH and long-range PCR.…”

Section: Introductionmentioning

confidence: 99%

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Identification and analysis of deletion breakpoints in four Mohr-Tranebjærg syndrome (MTS) patients

Rendtorff

Karstensen

Lodahl

et al. 2022

Sci Rep

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Mohr-Tranebjærg syndrome is an X-linked syndrome characterized by sensorineural hearing impairment in childhood, followed by progressive neurodegeneration leading to a broad phenotypic spectrum. Genetically MTS is caused by pathogenic variants in the TIMM8A gene, including gene deletions and larger contiguous gene deletions. Some of the latter involve the neighboring gene BTK, resulting in agammaglobulinemia. By next‐generation mate‐pair sequencing we have mapped the chromosomal deletion breakpoints of one MTS case and three XLA-MTS cases and used breakpoint-spanning PCR to fine map the breakpoints by Sanger sequencing. Two of the XLA-MTS cases presented with large deletions (63.5 and 27.2 kb), and the junctional regions were characterized by long stretches of microhomology, indicating that the events have emerged through homologous recombination. Conversely, the MTS case exhibited a small 2 bp region of microhomology, and the regions were not characterized by extensive microhomology. The third XLA-MTS case had a more complex breakpoint, including a 59 bp inverted insertion, thus at least four breakpoints were involved in this event. In conclusion, mate-pair library generation combined with next-generation sequencing is an efficient method for breakpoint identification, also in regions characterized by repetitive elements.

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“…The causative gene is translocase of mitochondrial inner membrane 8A ( TIMM8A ) /deafness dystonia protein 1 ( DDP1 ), which is located on Xq22.1 ( Tranebjærg, 1993 ; Tranebjaerg et al, 1995 ; Jin et al, 1996 ). Most of the disease-related mutations are frameshift or nonsense mutations leading to premature stops, while there are a few missense mutations ( Penamora-Destriza et al, 2015 ; Wang et al, 2019 ). Deafness-dystonia-optic neuronopathy syndrome mostly affects males and is less common among females due to X chromosome inactivation.…”

Section: Introductionmentioning

confidence: 99%

Reduced mitochondrial size in hippocampus and psychiatric behavioral changes in the mutant mice with homologous mutation of Timm8a1-I23fs49X

Ouattara

Chen

Huang

et al. 2022

Front. Cell. Neurosci.

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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.

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Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy

Cited by 14 publications

References 32 publications

Functional analysis of a novel mutation in the TIMM8A gene that causes deafness‐dystonia‐optic neuronopathy syndrome

Functional analysis of a novel mutation in the TIMM8A gene that causes deafness‐dystonia‐optic neuronopathy syndrome

Identification and analysis of deletion breakpoints in four Mohr-Tranebjærg syndrome (MTS) patients

Reduced mitochondrial size in hippocampus and psychiatric behavioral changes in the mutant mice with homologous mutation of Timm8a1-I23fs49X

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