Academic Journal
Targeted Next-Generation Sequencing of the Leptin-Melanocortin Pathway in Severe Obesity.
| Τίτλος: | Targeted Next-Generation Sequencing of the Leptin-Melanocortin Pathway in Severe Obesity. |
|---|---|
| Συγγραφείς: | Faccioli N; AP-HP, Trousseau Hospital, Department of Pediatric Nutrition and Gastroenterology, Reference Center for Rare Diseases PRADORT (Prader-Willi Syndrome and Other Rare Forms of Obesity With Eating Behavior Disorders), Sorbonne University, Paris, France.; INSERM, Nutrition and Obesity: Systemic Approaches, NutriOmics Research Unit, Sorbonne University, Paris, France., Poitou C; INSERM, Nutrition and Obesity: Systemic Approaches, NutriOmics Research Unit, Sorbonne University, Paris, France.; AP-HP, Pitie-Salpetriere Hospital, Nutrition Department, Reference Center for Rare Diseases (PRADORT, Prader-Willi Syndrome and Other Rare Forms of Obesity With Eating Behavior Disorders), Sorbonne University, Paris, France., Georget M; AP-HP, Pitie-Salpetriere Hospital, Functional Unit for the Genetics of Obesity and Dyslipidemia, Endocrine and Oncology Biochemistry Department, Sorbonne University, Paris, France., Bertin F; AP-HP, Pitie-Salpetriere Hospital, Functional Unit for the Genetics of Obesity and Dyslipidemia, Endocrine and Oncology Biochemistry Department, Sorbonne University, Paris, France., Azar-Kolakez A; Department of Pediatric Endocrinology and Diabetology, Reference Center for Growth and Development Endocrine Diseases, University Paris Cite, AP-HP, Robert Debre University Hospital, Paris, France., Carette C; AP-HP, Georges Pompidou European Hospital, Department of Nutrition, Specialized Obesity Centre & INSERM UMRS 1149, University Paris Cite, Paris, France., Faucher P; INSERM, Nutrition and Obesity: Systemic Approaches, NutriOmics Research Unit, Sorbonne University, Paris, France.; AP-HP, Pitie-Salpetriere Hospital, Nutrition Department, Reference Center for Rare Diseases (PRADORT, Prader-Willi Syndrome and Other Rare Forms of Obesity With Eating Behavior Disorders), Sorbonne University, Paris, France., Gatta-Cherifi B; Haut Leveque Hospital, Department of Endocrinology, Diabetology, Metabolic Diseases and Nutrition, University of Bordeaux, Pessac, France., Gonneau-Lejeune J; Félix-Guyon Hospital, Department of Pediatrics, Saint-Denis, University of La Reunion, Reunion, France., Linglart A; AP-HP, INSERM, Bicetre Paris Saclay Hospital, Endocrinology and Diabetology for Children, University Paris-Saclay, Le Kremlin-Bicetre, France., Clément K; INSERM, Nutrition and Obesity: Systemic Approaches, NutriOmics Research Unit, Sorbonne University, Paris, France.; AP-HP, Pitie-Salpetriere Hospital, Nutrition Department, Reference Center for Rare Diseases (PRADORT, Prader-Willi Syndrome and Other Rare Forms of Obesity With Eating Behavior Disorders), Sorbonne University, Paris, France., Le Beyec‐Le Bihan J; AP-HP, Pitie-Salpetriere Hospital, Functional Unit for the Genetics of Obesity and Dyslipidemia, Endocrine and Oncology Biochemistry Department, Sorbonne University, Paris, France.; INSERM, Center of Research on Inflammation, University Paris Cite, Paris, France., Dubern B; AP-HP, Trousseau Hospital, Department of Pediatric Nutrition and Gastroenterology, Reference Center for Rare Diseases PRADORT (Prader-Willi Syndrome and Other Rare Forms of Obesity With Eating Behavior Disorders), Sorbonne University, Paris, France.; INSERM, Nutrition and Obesity: Systemic Approaches, NutriOmics Research Unit, Sorbonne University, Paris, France. |
| Πηγή: | Obesity (Silver Spring, Md.) [Obesity (Silver Spring)] 2026 Feb; Vol. 34 (2), pp. 499-511. Date of Electronic Publication: 2025 Dec 26. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 101264860 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1930-739X (Electronic) Linking ISSN: 19307381 NLM ISO Abbreviation: Obesity (Silver Spring) Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2013- : Malden, MA : John Wiley & Sons Original Publication: Silver Spring, MD : NAASO, the Obesity Society, c2006- |
| Ιατρικοί όροι (MeSH): | Leptin*/genetics , Leptin*/metabolism , Obesity, Morbid*/genetics , Obesity, Morbid*/metabolism , Melanocortins*/genetics , Melanocortins*/metabolism, Receptor, Melanocortin, Type 4/genetics ; Receptors, Leptin/genetics ; Pro-Opiomelanocortin/genetics ; Proprotein Convertase 1/genetics ; Signal Transduction/genetics ; Humans ; Female ; Male ; High-Throughput Nucleotide Sequencing ; Child ; Adult ; Adolescent ; Retrospective Studies ; Child, Preschool ; Young Adult ; Age of Onset ; Middle Aged ; Phenotype |
| Περίληψη: | Objective: Pathogenic variants in five established leptin-melanocortin pathway genes (LEP, LEPR, MC4R, PCSK1, POMC) are associated with severe early-onset obesity and are targets for emerging treatments. However, these variants are rare in these patients, suggesting the involvement of additional genes interacting with this pathway. Methods: Next-generation sequencing (NGS) analysis was performed in 395 patients with severe obesity, including 213 children (mean BMI: 56.3 kg/m2; BMI-z-score: 4.6). The analysis targeted 20 genes, including the 5 established genes. Rare genetic variants were assessed for pathogenicity using prediction algorithms, genetic databases, and literature review. Phenotypic data were retrospectively collected, focusing on obesity severity, age of onset, familial history, eating behavior disorder, neurodevelopmental and endocrine-associated diseases, and obesity complications. Results: Pathogenic heterozygous variants were identified in 34 patients (8.6%), 18 of them harboring pathogenic variants in the 15 additional genes. In adults, early-onset obesity was more frequent in potentially pathogenic variants carriers than in non-carriers (83.3% vs. 55.0%, p = 0.04). No differences were observed in the other phenotypic characteristics. Conclusions: This supports the relevance of expanded genetic testing in severe obesity. Early-onset obesity remains a key clinical feature to guide genetic investigation and identify patients who may benefit from early personalized care and targeted treatments. (© 2025 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.) |
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| Grant Information: | 18000 € French Pediatric Society (Société Française de Pédiatrie) cofounded by Novo Nordisk Laboratory |
| Contributed Indexing: | Keywords: genetic obesity; personalized medicine; setmelanotide; syndromic obesity |
| Substance Nomenclature: | 0 (Leptin) 0 (Receptor, Melanocortin, Type 4) 0 (Receptors, Leptin) 66796-54-1 (Pro-Opiomelanocortin) 0 (MC4R protein, human) 0 (LEPR protein, human) 0 (LEP protein, human) EC 3.4.21.93 (Proprotein Convertase 1) EC 3.4.21.93 (PCSK1 protein, human) 0 (Melanocortins) |
| Entry Date(s): | Date Created: 20251226 Date Completed: 20260128 Latest Revision: 20260920 |
| Update Code: | 20260920 |
| PubMed Central ID: | PMC12850549 |
| DOI: | 10.1002/oby.70107 |
| PMID: | 41451896 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1930-739X |
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| DOI: | 10.1002/oby.70107 |