👤 Valentina Di Pietro

The rs12970134 variant near the melanocortin receptor 4 (MC4-R) has gained relevance suggesting an age dependent phenotypic effect in the induction of obesity in young age. A previous study evaluating 740 Caucasian children has shown this association in prepubertal children older than 8 years. The aim of this study was to assess whether the obesogenic effect of M4CR gene contributed to obesity also in adolescence. After 8 years participants of the original study were contacted and invited to perform an anthropometric evaluation. Out of 35 carriers of the AA risk allele of MC4-R, 12 subjects accepted to participate. Adolescent subjects with the AA risk allele of MC4-R were matched with 24 and 48 subjects, respectively for AG and GG variants. Differences between the three MC4-R genotypes for anthropometric data, for percentage of overweight and obesity and for changes in BMI-SDS over visit have been assessed. At Visit 1 (baseline examination study), the AA risk genotype was confirmed to be associated with higher BMI-SDS (1.3 ± 0.4 vs 0.4 ± 0.1) and waist circumference (66.5 ± 5.8 vs 60.9 ± 7.1) when compared to the GG genotype (p < 0.016 both). At Visit 2 the AA genotype not only was associated with a higher BMI-SDS (1.07 ± 0.5 vs 0.02 ± 0.8) and WC (95.6 ± 13.3 vs 64.9 ± 13.5) when compared to GG genotype, but also when compared to AG genotype (vs 0.5 ± 0.1 and 62.9 ± 10.0, p < 0.016). Whereas AA genotype demonstrated no change of BMI-SDS between visit 1 and visit 2 (p00.32), AG and GG genotype showed a significant reduction (p = 0.01 and 0.001 respectively). Furthermore, a higher percentage of patients were affected by overweight/obesity in the AA genotype compared to AG and GG genotypes (50% vs 20.8% vs 16.5% p = 0.03). This study demonstrates that the rs12970134 variant not only exerts an obesogenic influence in the prepubertal age but remains a major risk factor also during adolescence. Show less

Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a type of vacuolating leukodystrophy, which is mainly caused by mutations in MLC1 or GLIALCAM. The two MLC-causing genes encode for membrane proteins of yet unknown function that have been linked to the regulation of different chloride channels such as the ClC-2 and VRAC. To gain insight into the role of MLC proteins, we have determined the brain GlialCAM interacting proteome. The proteome includes different transporters and ion channels known to be involved in the regulation of brain homeostasis, proteins related to adhesion or signaling as several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptor GPR37L1. Focusing on these two GPCRs, we could validate that they interact directly with MLC proteins. The inactivation of Gpr37l1 in mice upregulated MLC proteins without altering their localization. Conversely, a reduction of GPRC5B levels in primary astrocytes downregulated MLC proteins, leading to an impaired activation of ClC-2 and VRAC. The interaction between the GPCRs and MLC1 was dynamically regulated upon changes in the osmolarity or potassium concentration. We propose that GlialCAM and MLC1 associate with different integral membrane proteins modulating their functions and acting as a recruitment site for various signaling components as the GPCRs identified here. We hypothesized that the GlialCAM/MLC1 complex is working as an adhesion molecule coupled to a tetraspanin-like molecule performing regulatory effects through direct binding or influencing signal transduction events. Show less

Traumatic brain injury (TBI) is set to become the leading cause of neurological disability across all age groups. Currently, no reliable biomarkers exist to help diagnose the severity of TBI to identify patients who are at risk of developing secondary injuries. Thus, the discovery of reliable biomarkers for the management of TBI would improve clinical interventions. Inflammatory markers are particularly suited for biomarker discovery as TBI leads to very early alterations in inflammatory proteins. Using the Proseek Multiplex Inflammation assay, we measured in patients that had suffered mild TBI (n = 10) or severe TBI (n = 10) with extra-cranial injury or extracranial injury only (EC) (n = 10), 92 inflammation-associated proteins in serum obtained: <1 hr (within 1-hour), 4-12 hr and 48-72 hr post injury. Changes were compared to healthy volunteers (HV). Our results identified CST5, AXIN1 and TRAIL as novel early biomarkers of TBI. CST5 identified patients with severe TBI from all other cohorts and importantly was able to do so within the first hour of injury. AXIN1 and TRAIL were able to discriminate between TBI and HV at <1 hr. We conclude that CST5, AXIN1 and TRAIL are worthy of further study in the context of a pre-hospital or pitch-side test to detect brain injury. Show less