학술논문
Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features.
Document Type
Academic Journal
Author
Benincá C; Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.; Department of Genetics, Federal University of Parana, Curitiba, Paraná, Brazil.; Zanette V; Department of Genetics, Federal University of Parana, Curitiba, Paraná, Brazil.; Brischigliaro M; Department of Biology, University of Padova, Padova, Veneto, Italy.; Johnson M; Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.; Reyes A; Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.; Valle DAD; Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Paraná, Brazil.; J Robinson A; Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.; Degiorgi A; Department of Chemistry, University of Parma, Parma, Emilia-Romagna, Italy.; Yeates A; Medical Research Council, Laboratory of Molecular Biology, Cambridge, Cambridgeshire, UK.; Telles BA; Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Paraná, Brazil.; Prudent J; Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.; Baruffini E; Department of Chemistry, University of Parma, Parma, Emilia-Romagna, Italy.; S F Santos ML; Neuropediatric Division, Hospital Pequeno Principe, Curitiba, Paraná, Brazil.; R de Souza RL; Department of Genetics, Federal University of Parana, Curitiba, Paraná, Brazil.; Fernandez-Vizarra E; Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.; Whitworth AJ; Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.; Zeviani M; Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK massimo.zeviani@unipd.it.; Department of Neurosciences, University of Padova, Padova, Veneto, Italy.
Source
Publisher: British Medical Association Country of Publication: England NLM ID: 2985087R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-6244 (Electronic) Linking ISSN: 00222593 NLM ISO Abbreviation: J Med Genet Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Mitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the 'mitoskeleton' due to its role in maintaining IMM architecture. APOO encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated.
Methods: We have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in APOO . Knockout models in Drosophila melanogaster and Saccharomyces cerevisiae were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.
Results: A likely pathogenic c.350T>C transition was found in APOO predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and D. melanogaster models.
Conclusion: This is the first case of pathogenic mutation in APOO , causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Methods: We have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in APOO . Knockout models in Drosophila melanogaster and Saccharomyces cerevisiae were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.
Results: A likely pathogenic c.350T>C transition was found in APOO predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and D. melanogaster models.
Conclusion: This is the first case of pathogenic mutation in APOO , causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)