Beninca 2020 J Med Genet
|Beninca C, Zanette V, Brischigliaro M, Johnson M, Reyes A, Valle DAD, Robinson AJ, Degiorgi A, Yeates A, Telles BA, Prudent J, Baruffini E, Santos ML, de Souza RL, Fernandez-Vizarra E, Whitworth A, Zeviani M (2020) Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features. J Med Genet [Epub ahead of print].|
Beninca C, Zanette V, Brischigliaro M, Johnson M, Reyes A, Valle DAD, Robinson AJ, Degiorgi A, Yeates A, Telles BA, Prudent J, Baruffini E, Santos ML, de Souza RL, Fernandez-Vizarra E, Whitworth A, Zeviani M (2020) J Med Genet
Abstract: 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.
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.
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.
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.
• Keywords: Clinical genetics, Genetics, Metabolic disorders, Neuromuscular disease • Bioblast editor: Plangger M
Labels: MiParea: Respiration, mt-Membrane, nDNA;cell genetics, Patients
Organism: Human Tissue;cell: Fibroblast Preparation: Intact cells
Coupling state: LEAK, ROUTINE, ET