Ayberk TÜRKYILMAZ, Oğuzhan YARAL, Erdal KURNAZ, Atilla ÇAYIR

Screening of MC4R, LEP, LEPR, POMC, SH2B1, and SIM1 genes in Turkish children with severe early-onset obesity

The aim of this study was to determine the prevalence of leptin (LEP), leptin receptors (LEPR), melanocortin-4-receptor (MC4R), proopiomelanocortin (POMC), single- minded 1 (SIM1), and SH2B1 gene variations in Turkish children and adolescents, and to conduct a detailed examination of the clinical and laboratory findings of patients with variants. In this study, we included 49 children and adolescents (29 male/20 female) who presented to the Pediatric Endocrinology clinic of Erzurum Regional Training and Research Hospital between 2017 and 2020 with obesity. Family history with regards to obesity, parental consanguinity, obesity-related comorbidities, anthropometric measurements, and laboratory tests of the patients were recorded in the clinical evaluation. LEP, LEPR, MC4R, POMC, SIM1, and SH2B1 genes, which are associated with monogenic obesity, were evaluated by the next generation sequencing analysis in all patients. The mean age of 49 patients included in the study was 8.4 ± 5.2 years (range: 0.6–16.8), their mean height standard deviation score (SDS) was 0.9 ± 1.6, mean body mass index (BMI) was 31.3 ± 8.1 kg/m2, and their mean BMI SDS was 3.5 ± 0.6. A total of four different variants (c.380C>T and c.870delG variants in MC4R gene; c.2992A>C and c.448delA variants in LEPR gene) were detected in four patients. The determination of a molecular etiology in patients with monogenic obesity is important in view of the treatment options to be introduced in the near future (MC4R agonist) and for the family to receive appropriate genetic counseling. In this study, we evaluated the clinical and genetic findings of the patients with monogenic obesity in detail, and contributed the findings of the novel variants to the literature.

PDF

___

GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377:13-27.,

Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet. 1997;27:325-51.

Thaker VV. Genetic and Epigenetic causes of obesity. Adolesc Med State Art Rev. 2017;28:379-405.

Huvenne H, Dubern B, Clément K, et al. Rare genetic forms of obesity: Clinical approach and current treatments in 2016. Obes Facts. 2016;9:158- 73.

Niazi RK, Gjesing AP, Hollensted M, et al. Identification of novel LEPR mutations in Pakistani families with morbid childhood obesity. BMC Med Genet. 2018;19:199.

Albuquerque D, Estévez MN, Víbora PB, et al. Novel variants in the MC4R and LEPR genes among severely obese children from the Iberian population. Ann Hum Genet. 2014;78:195-207.

Challis BG, Pritchard LE, Creemers JW, et al. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet. 2002;11:1997-2004.

Ramachandrappa S, Raimondo A, Cali AM, et al. Rare variants in singleminded 1 (SIM1) are associated with severe obesity. J Clin Invest 2013;123: 3042-50.

Doche ME, Bochukova EG, Su HW, et al. Human SH2B1 mutations are associated with maladaptive behaviors and obesity. J Clin Invest. 2012;122: 4732-6.

Chou K, Perry CM. Metreleptin: first global approval. Drugs. 2013;73:989- 997.

Kühnen P, Clément K, Wiegand S, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375: 240-6.

Chen KY, Muniyappa R, Abel BS, et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015;100:1639-45.

Neyzi O, Bundak R, Gökçay G, et al. Reference values for weight, height, head circumference, and body mass index in Turkish children. J Clin Res Pediatr Endocrinol. 2015;7:280-293.

Elkins C, Fruh S, Jones L, et al. Clinical practice recommendations for pediatric dyslipidemia. J Pediatr Health Care. 2019;33:494-504.

Shashaj B, Luciano R, Contoli B, et al. Reference ranges of HOMA-IR in normal-weight and obese young Caucasians. Acta Diabetol. 2016;53:251- 60.

Lee JM, Okumura MJ, Davis MM, et al. Prevalence and determinants of insulin resistance among U.S. adolescents: a population-based study. Diabetes Care. 2006;29:2427-32.

Bervoets L, Massa G. Classification and clinical characterization of metabolically “healthy” obese children and adolescents. J Pediatr Endocrinol Metab. 2016;29:553-60.

Kopanos C, Tsiolkas V, Kouris A, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978-80.

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.

Cooiman MI, Kleinendorst L, Aarts EO, et al. Genetic obesity and bariatric surgery outcome in 1014 patients with morbid obesity. Obes Surg. 2020;30: 470-7.

Akıncı A, Türkkahraman D, Tekedereli I, et al. Novel mutations in obesityrelated genes in Turkish children with non-syndromic early onset severe obesity: A multicentre study. J Clin Res Pediatr Endocrinol. 2019;11:341-9.

Tunç S, Demir K, Tükün FA, et al. Melanocortin-4 receptor gene mutations in a Group of english obese children and adolescents. J Clin Res Pediatr Endocrinol. 2017;9: 216-21.

Aykut A, Özen S, Gökşen D, et al. Melanocortin 4 receptor (MC4R) gene variants in children and adolescents having familial early-onset obesity: genetic and clinical characteristics. Eur J Pediatr. 2020;179:1445-52.

Lubrano-Berthelier C, Durand E, Dubern B, et al. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet. 2003;12:145-153.

Valli-Jaakola K, Lipsanen-Nyman M, Oksanen L, et al. Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults. J Clin Endocrinol Metab. 2004;89:940-5.

Bjørbaek C, Uotani S, da Silva B, et al. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem. 1997;272:32686- 95.

Huvenne H, Dubern B, Clément K, et al. Rare genetic forms of obesity: Clinical approach and current treatments in 2016. Obes Facts. 2016;9:158- 73.