Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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

Tian Zhao, Caitlin M. Goedhart, Pingdewinde Sam, Susanne Lingrell, Adam J. Cornish, Ryan E Lamont, Francois P Bernier, David Sinasac, Jillian S Parboosingh, Care4Rare Canada Consortium, Jean E. Vance, Steven M. Claypool, A Micheil Innes, Timothy E Shutt
doi: https://doi.org/10.1101/413070
Tian Zhao
1Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
2Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Caitlin M. Goedhart
1Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pingdewinde Sam
3Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susanne Lingrell
4Dept of Medicine and Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adam J. Cornish
3Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ryan E Lamont
1Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Francois P Bernier
1Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Sinasac
1Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jillian S Parboosingh
1Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean E. Vance
4Dept of Medicine and Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven M. Claypool
3Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A Micheil Innes
1Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy E Shutt
1Alberta Children’s Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
2Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

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 (PS) to phosphatidylethanolamine (PE) in the inner mitochondrial membrane (IMM). Decreased conversion of PS to PE, and depletion of total cellular PE levels in patient fibroblasts are consistent with impaired 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, restored mitochondrial and lysosome morphology in patient fibroblasts. Functional characterization of the PISD mutations 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 explains why the phenotypes of these PISD patients resemble recently described “mitochondrial chaperonopathies”. Collectively, these findings demonstrate that PISD is a novel mitochondrial disease gene.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted September 12, 2018.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes
Tian Zhao, Caitlin M. Goedhart, Pingdewinde Sam, Susanne Lingrell, Adam J. Cornish, Ryan E Lamont, Francois P Bernier, David Sinasac, Jillian S Parboosingh, Care4Rare Canada Consortium, Jean E. Vance, Steven M. Claypool, A Micheil Innes, Timothy E Shutt
bioRxiv 413070; doi: https://doi.org/10.1101/413070
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes
Tian Zhao, Caitlin M. Goedhart, Pingdewinde Sam, Susanne Lingrell, Adam J. Cornish, Ryan E Lamont, Francois P Bernier, David Sinasac, Jillian S Parboosingh, Care4Rare Canada Consortium, Jean E. Vance, Steven M. Claypool, A Micheil Innes, Timothy E Shutt
bioRxiv 413070; doi: https://doi.org/10.1101/413070

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Molecular Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (2653)
  • Biochemistry (5291)
  • Bioengineering (3701)
  • Bioinformatics (15840)
  • Biophysics (7289)
  • Cancer Biology (5650)
  • Cell Biology (8131)
  • Clinical Trials (138)
  • Developmental Biology (4791)
  • Ecology (7563)
  • Epidemiology (2059)
  • Evolutionary Biology (10621)
  • Genetics (7752)
  • Genomics (10175)
  • Immunology (5233)
  • Microbiology (13977)
  • Molecular Biology (5403)
  • Neuroscience (30911)
  • Paleontology (217)
  • Pathology (886)
  • Pharmacology and Toxicology (1527)
  • Physiology (2263)
  • Plant Biology (5043)
  • Scientific Communication and Education (1045)
  • Synthetic Biology (1401)
  • Systems Biology (4162)
  • Zoology (815)