Perturbations in Fatty Acid Metabolism and Collagen Production Infer Pathogenicity of a Novel MBTPS2 Variant in Osteogenesis Imperfecta

The study investigates the pathogenicity of a novel MBTPS2 variant, c.516A>C (p.Glu172Asp), in relation to Osteogenesis imperfecta (OI), a genetic bone disorder. MBTPS2 is known to cause X-linked recessive OI and other dermatological conditions. The researchers used fibroblasts from a male proband whose pregnancy was terminated at 21 weeks due to skeletal abnormalities. They performed transcriptional analyses, gas chromatography-tandem mass spectrometry for fatty acid quantification, and immunocytochemistry to assess fatty acid metabolism and collagen production. The results showed disruptions in fatty acid metabolism and reduced collagen deposition, similar to previous findings in MBTPS2-OI, confirming the pathogenicity of the MBTPS2 p.Glu172Asp variant in causing OI. This study underscores the importance of using molecular signatures from multiomics studies to evaluate the effects of novel genetic variants.