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oai:figshare.com:article/33992131 2026-09-25T04:26:07Z category_658 portal_316 item_type_3 month_year_09_2026

Table 1_Rare endocannabinoid system variants identified by whole-exome sequencing and structural modeling in adults with severe obesity predominantly of childhood onset.xlsx Kaio Cezar Rodrigues Salum (9747080) Ritiele Bastos de Souza (12491185) Deborah Antunes (6199022) Izadora Sthephanie da Silva Assis (18596596) Laura Wendling Gouvêa (25107139) Myrela Ribeiro Teixeira (25107142) Marília Alves Figueira de Melo (25107145) Lohanna Palhinha (8122697) Gabriella de Medeiros Abreu (9747086) Nathália da Silva Alves (25107148) Tamara Silva (20572700) Verônica Marques Zembrzuski (8558613) Mario Campos Junior (18596599) Clarissa Menezes Maya-Monteiro (3850936) Patrícia Torres Bozza (3174060) Ana Carolina Proença da Fonseca (9747104) João Regis Ivar Carneiro (3850930) Cell Metabolism childhood-onset obesity endocannabinoid system FAAH molecular modeling rare genetic variants Background<p>The endocannabinoid system (ECS) regulates key processes in energy homeostasis, but its contribution to severe obesity beginning in childhood or adolescence remains incompletely understood. This study aimed to identify rare variants in ECS genes and evaluate their potential structural effects.</p>Methods<p>A total of 93 adults with severe obesity beginning before 21 years of age (BMI ≥ 35 kg/m²) were recruited from two specialized obesity programs; among participants with onset information, 97.8% reported childhood onset. Whole-exome sequencing was performed, followed by targeted analysis of ECS-related genes. Rare variants (allele frequency <1%) were confirmed by Sanger sequencing and assessed using in silico pathogenicity prediction and molecular modeling. In silico saturation mutagenesis of all 19 possible substitutions at each variant position was additionally performed using three complementary stability predictors based on different methodological principles (FoldX, Pythia and DDMut), together with AlphaMissense.</p>Results<p>Nine rare variants were identified in twelve individuals, seven of which were defined as variants of uncertain significance (VUS). Among the observed variants, FAAH p.(Arg326Pro) showed the most concordant predicted impact: it ranked as the most destabilizing substitution at position 326 by FoldX (ΔΔG = +3.04 kcal/mol; rank 1 of 19) and was the only observed variant classified as likely pathogenic by AlphaMissense (0.884). Arg326 lies 24.3 Å from the catalytic triad (Lys142–Ser217–Ser241), consistent with a predicted effect on fold stability rather than direct disruption of the active site. Conversely, at DAGLA position 750, all 19 substitutions were predicted as neutral by FoldX and DDMut and as likely benign by AlphaMissense, consistent with predicted structural tolerance at this position. No anthropometric or metabolic parameter differed significantly between carriers and non-carriers after correction for multiple testing.</p>Conclusions<p>Rare ECS variants, including a previously unreported FAAH p.(Arg326Pro) substitution, were identified in adults with severe obesity, predominantly with childhood onset. These in silico analyses are predictive and provide computational evidence for prioritizing candidate variants, notably FAAH p.(Arg326Pro); they do not, by themselves, establish pathogenicity or a causal relationship with the phenotype, which will require functional validation.</p> 2026-09-25T04:26:07Z Dataset Dataset 10.3389/fendo.2026.1862926.s001 https://figshare.com/articles/dataset/Table_1_Rare_endocannabinoid_system_variants_identified_by_whole-exome_sequencing_and_structural_modeling_in_adults_with_severe_obesity_predominantly_of_childhood_onset_xlsx/33992131 CC BY 4.0