J Med Genet 2020 05 21. Epub 2020 May 21.
Medical Research Council, Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK
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. 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 . Knockout models in and were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.
Results: A likely pathogenic c.350T>C transition was found in 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 models.
Conclusion: This is the first case of pathogenic mutation in , causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.