The C2orf69 gene product is localized in the mitochondria mediated by a N-terminal 24 amino acid long signal peptide. Loss of C2orf69 leads to alterations in the OXPHOS (oxidative phosphorylation) and reduction of GBE1 glycogen-branching activity.
Suspected pathophysiologic mechanism
The loss of C2orf69, leads to reduced complex I, II and V activity of the OXPHOS. In line with this, a lower ATP production and respiration capacity are detected. Furthermore, the glycogen branching enzyme (GBE1) activity is reduced due to C2orf69 loss, which alter another pathway of the energy metabolism. On transcriptional level a compensatory upregulation of gene related to the OXPHOS process could be observed. On the other hand a strong dysregulation of immune-related pathways reflecting the autoimmune events of the patients could be seen.
Type of mutations
All so far described patients harbour bi-allelic loss-of-function mutations in C2orf69.
Genetic testing
As the known pathogenic mutations distribute among the whole gene (c.280-c.847) sequencing of the whole gene will be necessary. This can be either achieved by panel-based, exome or genome sequencing. The gene consist only of 2 exons, therefor sanger sequencing might be also an option in direct clinical suspicion. But as there is a strong overlap of the patient phenotype with other mitochondriopathies and immunopathies, an exome- or genome-wide approach will be most suitable for differential diagnosis.
Beside genetic testing, PAS (periodic acid–Schiff) staining of tissue sections might be helpful, as the glycogen deposits in the muscle and liver are a hallmark of the disease.
C2orf69