TY - JOUR T1 - <em>PISD</em> is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900353 VL - 2 IS - 2 SP - e201900353 AU - Tian Zhao AU - Caitlin M Goedhart AU - Pingdewinde N Sam AU - Rasha Sabouny AU - Susanne Lingrell AU - Adam J Cornish AU - Ryan E Lamont AU - Francois P Bernier AU - David Sinasac AU - Jillian S Parboosingh AU - Care4Rare Canada Consortium AU - Jean E Vance AU - Steven M Claypool AU - A Micheil Innes AU - Timothy E Shutt Y1 - 2019/04/01 UR - https://www.life-science-alliance.org/content/2/2/e201900353.abstract N2 - 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 “mitochondrial chaperonopathies.” Collectively, these findings demonstrate that PISD is a novel mitochondrial disease gene. ER -