RT Journal Article SR Electronic T1 PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201900353 DO 10.26508/lsa.201900353 VO 2 IS 2 A1 Tian Zhao A1 Caitlin M Goedhart A1 Pingdewinde N Sam A1 Rasha Sabouny A1 Susanne Lingrell A1 Adam J Cornish A1 Ryan E Lamont A1 Francois P Bernier A1 David Sinasac A1 Jillian S Parboosingh A1 Care4Rare Canada Consortium A1 Jean E Vance A1 Steven M Claypool A1 A Micheil Innes A1 Timothy E Shutt YR 2019 UL https://www.life-science-alliance.org/content/2/2/e201900353.abstract AB 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.