Transcriptomic and lipidomic profiling provide novel insight into the pathogenesis of monogenic SGMS2-related...

Heterozygous pathogenic variants in the SGMS2 gene, encoding the sphingomyelin-synthesizing enzyme sphingomyelin synthase 2, cause a rare monogenic form of osteoporosis with low bone density, fractures, bone deformities, sclerotic cranial lesions, and occasionally, neurological symptoms. Three disease-causing heterozygous SGMS2 variants have been reported: c.148C>T (p.Arg50*), c.185T>G (p.Ile62Ser), and c.191T>G (p.Met64Arg). This study examined the cellular mechanisms of SGMS2-related osteoporosis and skeletal dysplasia through transcriptomic and lipidomic profiling of serum and fibroblasts from patients and controls. Bulk RNA sequencing and SCIEX lipidyzer-based lipidomics were employed. Differential expression analysis revealed 215 upregulated and 58 downregulated genes enriched in 169 Gene Ontology Biological Processes related to skeletal, neurological, ocular, muscular, and membrane functions. Pathway analysis revealed enriched pathways associated with interleukin signaling, electrical transmission across gap junctions, and circadian clock. Four lipid metabolism pathways were enriched: PPARα regulation, glycerophospholipid biosynthesis, phospholipid metabolism, and lipid metabolism. Lipidome analysis failed to detect significant differences between fibroblasts of patients and controls, while revealing 55 upregulated lipids, predominantly triacylglycerols (TAGs), but no downregulated lipids in serum of the patients. These findings suggest that SGMS2 variants modulate circadian rhythm and gap junction assembly, adversely affecting bone health and homeostasis, and may affect neuron-supporting cells in SGMS2-related osteoporosis.