Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a recessive genetic disease. Affected individuals present musculoskeletal abnormalities, insulin resistance, hepatic steatosis, and may develop cardiomyopathy and mental retardation The mechanism linking AGPAT2 (for CGL1) and BSCL2 (for CGL2) mutations to the syndrome has yet to be fully understood.

Here, we analyzed blood cell transcriptomes from individuals with CGL1 (n = 3), CGL2 (n = 12), unaffected BSCL2 heterozygotes (HET, n = 8), and healthy individuals (CTRL, n = 3). Study participants were also evaluated by densitometry (GE Lunar DPX), in addition to biochemical panel and pro-inflammatory cytokines measured in serum.

The gene expression profile of CGL1 was similar to CTRL, a result likely due to the compensatory activity of other AGPAT isoforms. CGL2 had 283 differentially expressed genes (DEGs), most enriched for neurodegenerative- and mitochondria-related genes. There was a negative correlation between the top1 gene, NUAK2, and fat mass (rho = −0.55, p = 0.01). The HET group had 105 DEGs, with OLR1, an atherogenic gene, as the most significant (Padj = 0.003). Up-regulation of TNF signaling pathway was also detected, a finding confirmed by high TNF and low IL10 levels in serum.

Both CGL2 individuals and their unaffected relatives had abnormal gene expression pattern. Further epidemiological studies should seek to assess cardiovascular risk in heterozygote individuals.