Functional analysis of a novel mutation in the TIMM8A gene that causes deafness-dystonia-optic neuronopathy syndrome.
Cells, Cultured
Child, Preschool
Deaf-Blind Disorders
/ genetics
Dystonia
/ genetics
Fibroblasts
/ metabolism
Humans
Intellectual Disability
/ genetics
Male
Membrane Transport Proteins
/ genetics
Mitochondria
/ metabolism
Mitochondrial Precursor Protein Import Complex Proteins
Mutation
Optic Atrophy
/ genetics
TIMM8A gene
X chromosome
deafness-dystonia-optic neuronopathy syndrome Mohr-Tranebjaerg syndrome
mitochondrial inner membrane
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
21
11
2019
revised:
20
12
2019
accepted:
23
12
2019
pubmed:
7
1
2020
medline:
30
3
2021
entrez:
7
1
2020
Statut:
ppublish
Résumé
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. 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. 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. This case expands the spectrum of mutations that cause DDON syndrome and demonstrates effects on mitochondrial morphology that are consistent with prior reports.
Sections du résumé
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.
Identifiants
pubmed: 31903733
doi: 10.1002/mgg3.1121
pmc: PMC7057109
doi:
Substances chimiques
Membrane Transport Proteins
0
Mitochondrial Precursor Protein Import Complex Proteins
0
TIMM8A protein, human
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1121Informations de copyright
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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