TY - JOUR T1 - Mutation in the MICOS subunit gene <em>APOO</em> (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features JF - Journal of Medical Genetics JO - J Med Genet SP - 155 LP - 167 DO - 10.1136/jmedgenet-2020-106861 VL - 58 IS - 3 AU - Cristiane Benincá AU - Vanessa Zanette AU - Michele Brischigliaro AU - Mark Johnson AU - Aurelio Reyes AU - Daniel Almeida do Valle AU - Alan J. Robinson AU - Andrea Degiorgi AU - Anna Yeates AU - Bruno Augusto Telles AU - Julien Prudent AU - Enrico Baruffini AU - Mara Lucia S. F. Santos AU - Ricardo Lehtonen R. de Souza AU - Erika Fernandez-Vizarra AU - Alexander J. Whitworth AU - Massimo Zeviani Y1 - 2021/03/01 UR - http://jmg.bmj.com/content/58/3/155.abstract N2 - 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&gt;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. ER -