PISDis a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes

AbstractExome sequencing of two sisters with congenital cataracts, short stature and white matter changes identified compound heterozygous variants in thePISDgene, encoding the phosphatidylserine decarboxylase enzyme that converts phosphatidylserine (PS) to phosphatidylethanolamine (PE) in the inner mitochondrial membrane (IMM). Decreased conversion of PS to PE, and depletion of total cellular PE levels in patient fibroblasts are consistent with impaired PISD enzyme activity. Meanwhile, as evidence for mitochondrial dysfunction, patient fibroblasts exhibited more fragmented mitochondrial networks, enlarged lysosomes, decreased maximal oxygen consumption rates and increased sensitivity to 2-deoxyglucose. Moreover, treatment with lyso-PE, which can replenish the mitochondrial pool of PE, restored mitochondrial and lysosome morphology in patient fibroblasts. Functional characterization of thePISDmutations demonstrates that the maternal variant causes an alternative splice product. Meanwhile, the paternal variant impairs autocatalytic self-processing of the PISD protein required for its activity. Finally, evidence for impaired activity of mitochondrial IMM proteases explains why the phenotypes of thesePISDpatients resemble recently described “mitochondrial chaperonopathies”. Collectively, these findings demonstrate thatPISDis a novel mitochondrial disease gene.