PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes
| Autor: | Tian Zhao, Caitlin Goedhart, Jillian S. Parboosingh, Jean E. Vance, Timothy E. Shutt, David S. Sinasac, Ryan E. Lamont, Adam J Cornish, A. Micheil Innes, Pingdewinde N. Sam, Steven M. Claypool, Rasha Sabouny, Susanne Lingrell, Francois P. Bernier |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Health
Toxicology and Mutagenesis Mitochondrial disease Plant Science Biology Compound heterozygosity Biochemistry Genetics and Molecular Biology (miscellaneous) 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Lysosome medicine Inner mitochondrial membrane Research Articles 030304 developmental biology Phosphatidylethanolamine 0303 health sciences Ecology Phosphatidylserine Transfection medicine.disease Cell biology medicine.anatomical_structure chemistry sense organs 030217 neurology & neurosurgery Phosphatidylserine decarboxylase Research Article |
| Zdroj: | Life Science Alliance |
| ISSN: | 2575-1077 |
| Popis: | This work demonstrates that pathogenic variants in PISD cause mitochondrial disease and suggests a novel mechanistic link whereby impaired lipid content in the inner mitochondrial membrane alters the activity of inner mitochondrial membrane proteases. 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. |
| Databáze: | OpenAIRE |
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