ESPEYB21 11. Obesity and Weight Regulation Genetic Risk Score and New Genes (2 abstracts)
11.10. Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease
Zhao Y , Chukanova M , Kentistou KA , Fairhurst-Hunter Z , Siegert AM , Jia RY , Dowsett GKC , Gardner EJ , Lawler K , Day FR , Kaisinger LR , Tung YCL , Yee Hong Lam B , Chen HJC , Wang Q , Berumen-Campos J , Kuri-Morales P , Tapia-Conyer R , Alegre-Diaz J , Barroso I , Emberson J , Torres JM , Collins R , Saleheen D , Smith KR , Paul DS , Merkle F , Farooqi IS , Wareham NJ , Petrovski S , O’Rahilly S , Ong KK , Yeo GSH & Perry JRB
MRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, School of Clinical Medicine, Cambridge, UK.
John.Perry@mrc-epid.cam.ac.uk
Nat Genet 56, 579–584 (2024). https://doi.org/10.1038/s41588-024-01694-x, https://pubmed.ncbi.nlm.nih.gov/38575728/
Brief Summary: This exome-wide association study conducted in the UK Biobank cohort (n=454 787) and in two non-European cohorts, the Mexican MCPS cohort (n=141 046) and the Pakistani PGR cohort (n=37 800), identified a association between rare protein-truncating variants (PTVs) in the APBA1 and the BSN genes and adult-onset obesity, suggesting two new genes as possible causes for monogenic obesity. Rare PTVs in BSN were also associated with Type 2 diabetes and fatty liver disease. Screening for rare PTVs in APBA1 and BSN in the Severe Childhood-Onset Obesity Project (SCOOP) cohort (n=927) detected 3 individuals with rare PTVs in BSN.
Identification of genes and genetic variants as possible causes for monogenic obesity is important for gaining new insights into weight regulation pathways and consequently new therapeutic strategies. In contrast to previously described forms of monogenic obesity, characterized by early-childhood obesity, this study examined genetic variants causing adult-onset obesity in 3 populations of different ethnicity. APBA1 is involved in signal transduction in the central nervous system [1] and in glucose homeostasis [2,3]. In vitro experiments in stem cell-derived hypothalamic neurons with PTVs in BSN revealed a reduced expression of SEMA3C which causes obesity in animal models through interfering with the leptin-melanocortin pathway [4]. Thus, PTVs in these genes could potentially cause obesity before adulthood, as shown by the appearance of rare PTVs in BSN in the SCOOP cohort. In a separate paper, Zhu et al. reported 2 cases with rare loss-of-function variants in BSN who had obesity in teenage years [5], suggesting that variants in BSN may cause obesity before reaching adulthood. Taken together, these considerations support the suspicion that rare PTVs in BSN and APBA1 are associated with adult-onset obesity but may be relevant for early-onset obesity and should be included in diagnostic panel testing for monogenic forms of obesity in both children and adults.
References: 1. Butz S, Okamoto M, Südhof TC. A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell. 1998 Sep 18;94(6):773-82. doi:10.1016/s0092-8674(00)81736-5.2. Zhang K, Wang T, Liu X, Yuan Q, Xiao T, Yuan X, Zhang Y, Yuan L, Wang Y. CASK, APBA1, and STXBP1 collaborate during insulin secretion. Mol Cell Endocrinol. 2021 Jan 15;520:111076. doi:10.1016/j.mce.2020.111076.3. Mondal T, Loffredo CA, Simhadri J, Nunlee-Bland G, Korba B, Johnson J, Cotin S, Moses G, Quartey R, Howell CD, Noreen Z, Arif M, Ghosh S. Insights on the pathogenesis of type 2 diabetes as revealed by signature genomic classifiers in an African American population in the Washington, DC area. Diabetes Metab Res Rev. 2023; 39(1):e3589. doi:10.1002/dmrr.3589.4. van der Klaauw AA, Croizier S, Mendes de Oliveira E, Stadler LKJ, Park S, Kong Y, Banton MC, Tandon P, Hendricks AE, Keogh JM, Riley SE, Papadia S, Henning E, Bounds R, Bochukova EG, Mistry V, O’Rahilly S, Simerly RB, Minchin JEN, Barroso I, Jones EY, Bouret SG, Farooqi IS. Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance. Cell. 2019 Feb 7;176(4):729-742.e18. doi:10.1016/j.cell.2018.12.009.5. Zhu N, LeDuc CA, Fennoy I, Laferrère B, Doege CA, Shen Y, Chung WK, Leibel RL. Rare predicted loss of function alleles in Bassoon (BSN) are associated with obesity. npj Genomic Medicine 2023, 8:33. doi:10.1038/s41525-023-00376-7.
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