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

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 2deoxyglucose. 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.

The R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy

“…Mitochondrial membrane potential and mitochondrial mass were assessed in control and patient fibroblasts by flow cytometry, as described previously [34]. Briefly, fibroblasts were seeded at 1 × 10 5 cells in 6 well plates and allowed to grow for 2 days.…”

PE homeostasis rebalanced through mitochondria-ER lipid exchange prevents retinal degeneration in Drosophila

“…In particular, mutations in PISD, the human counterpart of fly PSD, cause Liberfarb syndrome, which is a multisystem disorder affecting the eyes, ears, bone, and brain [ 22 ]. Studies in patient-derived fibroblasts revealed impaired phospholipid metabolism, altered mitochondrial respiration, and fragmentation of the mitochondrial network [ 20 , 21 ]. Recently, mutations in PCYT2, the human counterpart of fly PECT, have been associated with hereditary spastic paraplegia.…”

“…Recently, a hypomorphic mutation in PCYT2 (a component of the CDP-ethanolamine pathway) was shown to cause recessive forms of progressive neurodegeneration, namely spastic paraplegia disorders [ 7 ]. Homozygous mutations in PSD genes cause a range of conditions, including skeletal dysplasia, early-onset retinal degeneration, hearing loss, microcephaly, and intellectual disability [ 20 – 22 ]. It is clear therefore that both PE biosynthesis pathways are crucial for the function and survival of neurons.…”

Hypothesis: Chemical activity regulates and coordinates the processes maintaining glycerophospholipid homeostasis in mammalian cells

“…Glycerophospholipids (GPLs) form the backbone of all membranes in mammalian cells. The major GPL classes are phosphatidylcholine (PC), ‐ethanolamine (PE), ‐inositol (PI), ‐serine (PS), ‐glycerol (PG), phosphatidic acid (PA) and cardiolipin (CL) and the relative concentrations (mole fractions) of these GPLs are kept within close limits in mammalian cells and tissues apparently because deviations from the “optimal” composition can have dire consequences . Remarkably, however, despite the vital importance of GPL homeostasis, the mechanisms underlying this crucial phenomenon is poorly understood, except for that biosynthesis and degradation are tightly coordinated.…”