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

<div><p>Background</p><p>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 <i>SIM1</i> mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of <i>SIM1</i> in severely obese children of Slovak and Moravian descent to determine if genetic variants within <i>SIM1</i> may influence the development of obesity in these populations.</p><p>Methods</p><p>The <i>SIM1</i> 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 <i>SIM1</i> variant carriers were compared with clinical phenotypes of 4 <i>MC4R</i> variant carriers and with 27 unrelated <i>SIM1</i> and <i>MC4R</i> mutation negative obese controls that were matched for age and gender.</p><p>Results</p><p>Seven previously described <i>SIM1</i> variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7 <i>in silico</i> 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 (<i>p</i> = 0.02) and low fat, low carbohydrate, high protein (<i>p</i> = 0.02) foods compared to the obese controls.</p><p>Conclusions</p><p>We have identified a novel <i>SIM1</i> variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.</p></div

Distribution of <i>SIM1</i> variants among carriers and <i>in silico</i> analyses.

<p>Distribution of <i>SIM1</i> variants among carriers and <i>in silico</i> analyses.</p

Pedigree of the family with the novel <i>SIM1</i> variant p.D134N.

<p>Squares represent males; circles represent females; filled symbols indicate obese individuals. Proband is indicated by an arrow. The text below each individual indicates mutational status (NM—heterozygous p.D134N carrier; NN—non-carrier), age at diagnosis of obesity, current age, and BMI (BMI SDS). ND—not determined.</p

Food preference for the novel SIM1 variant p.D134N carriers (proband, her father and brother) compared to unrelated obese adult controls.

<p>A) Food preference for the low fat, low carbohydrate and high protein food and B) Food preference for the high sugar food.</p

Genotype and phenotype characteristics in the proband with the novel p.D134N variant and her family members.

<p>Genotype and phenotype characteristics in the proband with the novel p.D134N variant and her family members.</p