BACKGROUND: Inactivating 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. METHODS: The 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. RESULTS: Seven 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. CONCLUSIONS: We 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.

Department of Biomedical Sciences Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Internal Medicine Jessenius Medical Faculty of Comenius University Martin Slovakia

Department of Pediatrics Medical Faculty of Comenius University Bratislava Slovakia

Department of Pediatrics Medical Faculty of Safarik University Kosice Slovakia

Department of Pediatrics Vitkovice Hospital Ostrava Czech Republic

Department of Physiology and Pathophysiology Faculty of Medicine University of Ostrava Ostrava Czech Republic

Laboratory of Diabetes and Metabolic Disorders Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia

Laboratory of Diabetes and Metabolic Disorders Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia Department of Pediatrics Medical Faculty of Comenius University Bratislava Slovakia Center for Pediatric Research Leipzig University Hospital for Children and Adolescents University of Leipzig Leipzig Germany

Laboratory of Diabetes and Metabolic Disorders Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia Department of Pediatrics Medical Faculty of Comenius University Bratislava Slovakia Institute of Social Medicine Occupational Health and Public Health University of Leipzig Leipzig Germany

Laboratory of Diabetes and Metabolic Disorders Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia Institute of Pathophysiolgy Faculty of Medicine Comenius University Bratislava Slovakia

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