NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect

textabstractMitochondrial respiratory chain complexI consists of 44 different subunits and contains 3 functional modules: the Q-, the N- and the P-module. NDUFA9is a Q-module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. So far, a single patient carrying an NDUFA9variant with a severe neonatally fatal phenotypehas been reported. Via exome sequencing, we identified a novel homozygous NDUFA9missense variant in another patient with a milder phenotypeincluding childhood-onset progressive generalized dystonia and axonal peripheral neuropathy. We performed complex I assembly analysis using primary skin fibroblasts of both patients. Reduced complex I abundance and an accumulation of Q-module subassemblies were present in both patients but more pronounced in the severe clinical phenotypepatient. The latter displayed additional accumulation of P-module subassemblies, which was not present in the milder- phenotypepatient. Lentiviral complementation of both patient fibroblast cell lines with wild-type NDUFA9rescued complex I deficiency and the assembly defects. Our report further characterizes the phenotypicspectrum of NDUFA9deficiency and demonstrates that the severity of the clinical phenotypecorrelates with the severity of the effects of the different NDUFA9variants on complex I assembly.