A Novel Human Heterozygous SCP2 Mutation Leads to Alterations in Lipid Metabolism.

Peroxisomal β-oxidation plays a critical role in the detoxification of fatty acids and in cholesterol metabolism to form bile acids. The sterol carrier protein-x (SCPx) is a lipid transfer protein with thiolase activity catalyzing the final step of the peroxisomal β-oxidation process. SCPx deficiency has been previously reported in only two patients. Here, we report the third patient with SCPx deficiency and the first resulting from a heterozygous mutation in the SCP2gene encoding SCPx. The patient presented with azoospermia, cardiac dysrhythmia, muscle wasting, and progressive brainstem neurodegeneration. The objective of this work was to investigate the link between the patient's SCP2mutation and his clinical presentations. We hypothesized that, because SCPx plays a critical role in the transport and metabolism of many lipids, the patient's SCP2 mutation could lead to widespread alterations in lipid-related genes and their target pathways. Patient fibroblasts (WESP) and normal human dermal fibroblasts (NHDF) were used to investigate the effects of the SCP2 mutation. RNA sequencing was used to identify lipid-related differentially expressed genes, which led to the identification of metabolic pathways affected by the patient's SCP2 mutation including cholesterol metabolism, peroxisome proliferator-activated receptor (PPAR) signaling, and serotonergic synapse signaling. Lipidomic analyses were used to identify changes in the levels of various lipids including several sterols, free fatty acids, phospholipids, and acylcarnitines. This led to the identification of other affected metabolic pathways including steroid biosynthesis, bile acid metabolism, and fatty acid degradation. Collectively, these findings show that the patient's heterozygous mutation in SCP2 led to alterations in several lipid metabolic pathways, which may explain certain clinical consequences of SCPx deficiency.