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

Life Sci Alliance. 2019 Mar 11;2(2):e201900353. doi: 10.26508/lsa.201900353.

Tian Zhao ¹ ², Caitlin M Goedhart ¹, Pingdewinde N Sam ³, Rasha Sabouny ¹ ², Susanne Lingrell ⁴, Adam J Cornish ³, Ryan E Lamont ¹, Francois P Bernier ¹ ⁵, David Sinasac ¹, Jillian S Parboosingh ¹, Care4Rare Canada Consortium, Jean E Vance ⁴, Steven M Claypool ³, A Micheil Innes ⁶ ⁷ ⁵, Timothy E Shutt ⁸ ² ⁷

Affiliations

1 Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
2 Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
3 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4 Department of Medicine and Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada.
5 Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
6 Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada micheil.innes@ahs.ca.
7 Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
8 Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada timothy.shutt@ucalgary.ca.

PMID: 30858161 DOI: 10.26508/lsa.201900353

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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