Changes in redox and endoplasmic reticulum homeostasis are related to congenital generalized lipodystrophy type 2.

CGL type 2 is a rare autosomal recessive syndrome characterized by an almost complete lack of body fat. CGL is caused by loss-of-function mutations in both alleles of the BSCL2 gene that codifies to seipin. Subjects often show hyperglycemia, decreased HDL-c, and hypoadiponectinemia. These laboratory findings are important triggers for changes in redox and ER homeostasis. Therefore, our aim was to investigate whether these intracellular mechanisms are associated with this syndrome. We collected blood from people from Northeastern Brazil with 0, 1, and 2 mutant alleles for the rs786205071 in the BSCL2 gene. Through the qPCR technique, we evaluated the expression of genes responsible for triggering the antioxidant response, DNA repair, and ER stress in leukocytes. Colorimetric tests were applied to quantify lipid peroxidation and to evaluate the redox status of glutathione, as well as to access the panorama of energy metabolism. Long extension PCR was performed to observe leukocyte mitochondrial DNA lesions, and the immunoblot technique to investigate plasma adiponectin concentrations. Subjects with the rs786205071 in both BSCL2 alleles showed increased transcription of NFE2L2, APEX1, and OGG1 in leukocytes, as well as high concentrations of malondialdehyde and the GSSG:GSH ratio in plasma. We also observed increase of mitochondrial DNA lesions and XBP1 splicing, as well as a decrease in adiponectin and HDL-c. Our data suggest the presence of lipid lesions due to changes in redox homeostasis in that group, associated with increased levels of mitochondrial DNA damage and transcriptional activation of genes involved with antioxidant response and DNA repair.

The worldwide mutational landscape of Berardinelli-Seip congenital lipodystrophy.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare disease characterized by the near total absence of body fat at birth. BSCL etiology involves genetic variations in four different genes: AGPAT2, BSCL2, CAV1, and CAVIN1. The four different biochemical subtypes of the disease are distinguished depending on which gene is mutated. The diagnosis of lipodystrophy can be based on clinical criteria, but the gold standard remains genetic testing. Since many different mutations have already been correlated with the onset of the disease, the most indicative method is DNA sequencing. However, not all laboratories have the resources to perform sequencing. Thus, less expensive techniques that include narrow gene regions may be applied. In such cases, the target mutations to be tested must be carefully determined taking into account the frequency of the description of the mutations in the literature, the nationality of the patient, as well as their phenotype. This review considers the molecular basis of BSCL, including the manual count of the majority of mutations reported in the literature up to the year 2018. Ninety different genetic mutations in 332 cases were reported at different frequencies. Some mutations were distributed homogeneously and others were specific to geographic regions. Type 2 BSCL was mentioned most often in the literature (50.3% of the cases), followed by Type 1 (38.0%), Type 4 (10.2%), and Type 3 (1.5%). The mutations comprised frameshifts (34.4%), nonsense (26.6%), and missense (21.1%). The c.517dupA in the BSCL2 gene was the most frequent (13.3%), followed by c.589-2A>G in the AGPAT2 gene (11.5%), c.507_511delGTATC in the BSCL2 gene (9.7%), c.317-588del in the AGPAT2 gene (7.3%), and c.202C>T in the AGPAT2 gene (4.5%). This information should prove valuable for analysts in making decisions regarding the best therapeutic targets in a population-specific context, which will benefit patients and enable faster and less expensive treatment.