@article {Zhaoe201900353, author = {Tian Zhao and Caitlin M Goedhart and Pingdewinde N Sam and Rasha Sabouny and Susanne Lingrell and Adam J Cornish and Ryan E Lamont and Francois P Bernier and David Sinasac and Jillian S Parboosingh and Care4Rare Canada Consortium and Jean E Vance and Steven M Claypool and A Micheil Innes and Timothy E Shutt}, title = {PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes}, volume = {2}, number = {2}, elocation-id = {e201900353}, year = {2019}, doi = {10.26508/lsa.201900353}, publisher = {Life Science Alliance}, abstract = {Exome sequencing of two sisters with congenital cataracts, short stature, and white matter changes identified compound heterozygous variants in the PISD gene, encoding the phosphatidylserine decarboxylase enzyme that converts phosphatidylserine to phosphatidylethanolamine (PE) in the inner mitochondrial membrane (IMM). Decreased conversion of phosphatidylserine to PE in patient fibroblasts is consistent with impaired phosphatidylserine decarboxylase (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, and genetic complementation restored mitochondrial and lysosome morphology in patient fibroblasts. Functional characterization of the PISD variants 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 suggests an explanation as to why the phenotypes of these PISD patients resemble recently described {\textquotedblleft}mitochondrial chaperonopathies.{\textquotedblright} Collectively, these findings demonstrate that PISD is a novel mitochondrial disease gene.}, URL = {https://www.life-science-alliance.org/content/2/2/e201900353}, eprint = {https://www.life-science-alliance.org/content/2/2/e201900353.full.pdf}, journal = {Life Science Alliance} }