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.
Highlights
The clinical phenotypes of the SIM1 variant carriers were compared with clinical phenotypes of 4 melanocortin 4 receptor (MC4R) variant carriers and with 27 unrelated SIM1 and MC4R mutation negative obese controls that were matched for age and gender
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
We have identified a novel SIM1 variant, p.D134N, in 4 obese individuals from a single pedigree which is associated with lower preference for certain foods
Summary
Single minded 1 (SIM1) is a bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) transcription factor that forms a functional dimer with another bHLH/PAS family member, ARNT2 [1]. SIM1 mutations seem to be involved in the pathogenesis of obesity; for example, a balanced translocation disrupting the SIM1 gene was found in a girl with severe non-syndromic early-onset obesity [5], and patients with 6q deletions encompassing the SIM1 gene present with Prader-Willi-like phenotypes including obesity and developmental delay [6]. Similar to MC4R mutation carriers, SIM1 mutation carriers have early-onset obesity caused by increased appetite and food seeking behavior persisting into adulthood [7,9]. The contribution of SIM1 variants to early-onset obesity have so far only been studied in a few populations [7,8,10]. Inactivating mutations of the hypothalamic transcription factor singleminded (SIM1) have been shown as a cause of early-onset severe obesity. To date, the contribution of SIM1 mutations to the obesity phenotype has only been studied in a few populations. 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
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