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

Care4Rare Canada Consortium

Research output: Contribution to journalArticle

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 “mitochondrial chaperonopathies.” Collectively, these findings demonstrate that PISD is a novel mitochondrial disease gene.

Original languageEnglish (US)
Article numbere201900353
JournalLife Science Alliance
Volume2
Issue number2
DOIs
StatePublished - Jan 1 2019

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Mitochondrial Diseases
phosphatidylserines
Mitochondrial Genes
cataract
Cataract
Genes
membrane
gene
oxygen consumption
phosphatidylethanolamines
Fibroblasts
enzyme activity
phenotype
genes
enzyme
Phosphatidylserines
Mitochondrial Membranes
protein
fibroblasts
Lysosomes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Plant Science
  • Ecology
  • Health, Toxicology and Mutagenesis

Cite this

PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. / Care4Rare Canada Consortium.

In: Life Science Alliance, Vol. 2, No. 2, e201900353, 01.01.2019.

Research output: Contribution to journalArticle

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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 “mitochondrial chaperonopathies.” Collectively, these findings demonstrate that PISD is a novel mitochondrial disease gene.",
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AU - Sabouny, Rasha

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AU - Cornish, Adam J.

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AU - Bernier, Francois P.

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