PR002145 (Project)

Description:Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by a heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant have been less investigated. We report here the first homozygous CHCHD10 patient, with variant p.G66V. We compare the metabolome of heterozygous and homozygous SMAJ patient skin fibroblasts, and in motor neurons differentiated from patient-specific stem cells as well as introduce a novel mouse model of SMAJ. Our findings show that p.G66V variant leads to dose-dependent reduction of the CHCHD10 protein in a cell type specific manner. In addition, CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism. The identification of the metabolites was based on a pipeline built using standardized pure metabolites. Some metabolites were not detected in all samples, even though they were detected in standardized control samples.