Genetic analysis of single-minded 1 gene in early-onset severely obese children and adolescents

Abstract

BackgroundInactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of SIM1 mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of SIM1 in severely obese children of Slovak and Moravian descent to determine if genetic variants within SIM1 may influence the development of obesity in these populations.MethodsThe SIM1 promoter region, exons and exon-intron boundaries were sequenced in 126 unrelated obese children and adolescents (2–18 years of age) and 41 adult lean controls of Slovak and Moravian origin. Inclusion criteria for the children and adolescents were a body mass index standard deviation score higher than 2 SD for an appropriate age and sex, and obesity onset at less than 5 years of age. The clinical phenotypes of the SIM1 variant carriers were compared with clinical phenotypes of 4 MC4R variant carriers and with 27 unrelated SIM1 and MC4R mutation negative obese controls that were matched for age and gender.ResultsSeven previously described SIM1 variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7 in silico software analyses and is located at a highly conserved position of the SIM1 protein. The p.D134N variant was found in an 18 year old female proband (BMI 44.2kg/m2; +7.5 SD), and in 3 obese family members. Regardless of early onset severe obesity, the proband and her brother (age 16 years) did not fulfill the criteria of metabolic syndrome. Moreover, the variant carriers had significantly lower preferences for high sugar (p = 0.02) and low fat, low carbohydrate, high protein (p = 0.02) foods compared to the obese controls.ConclusionsWe have identified a novel SIM1 variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.

Genetics and epigenetics in the obesity phenotyping scenario

“…Loss-of-function mutations in the gene encoding the transcription factor ‘Single-minded homolog of drosophila ’ (SIM1) lead to changes in feeding behavior and extreme obesity [ 37 , 94 ]. Furthermore, a novel SIM1 variant, p.D134N, has been recently implicated in monogenic pediatric obesity [ 95 ].…”

Genetics, epigenetics and transgenerational transmission of obesity in children

“…Moreover, few point mutations in SIM1 have been recognized as a cause of monogenic obesity ( 43 , 44 ). A novel SIM1 variant, p.D134N, potentially linked to monogenic pediatric obesity has been recently identified by Stanikova et al, in a cohort of children and adolescents ( 45 ). In addition, dominant forms of non-syndromic monogenic obesity in humans have been associated with mutations in BDNF gene, encoding for the protein involved in proliferation and survival of hypothalamic neurons ( 46 ).…”

Reviewed and updated Algorithm for Genetic Characterization of Syndromic Obesity Phenotypes

“…The activation of MC4R receptors induces the expression of the Brain-derived Neurotrophic Factor (encoded by the BDNF gene) [ 75 ] through the cyclic AMP-protein kinase A signaling pathway, in which Adenylate Cyclase 3 (encoded by the ADCY3 gene) has a crucial role [ 75 - 77 ]. This MC4R activity is facilitated by Single-minded 1 (encoded by the SIM1 gene) [ 78 ]. Finally, BDNF activates the Neurotrophic receptor Tyrosine kinase 2 (encoded by NTRK2 ) [ 79 ] which results in the liberation of oxytocin in the PVN of the hypothalamus, causing activation of fatty acids β-oxidation and a clear response in the organism; an increase in energy expenditure and a decrease in food intake [ 59 ].…”