早发性重度肥胖儿童及青少年中单 minded 1 基因的遗传分析。
Genetic analysis of single-minded 1 gene in early-onset severely obese children and adolescents.
作者信息
Stanikova Daniela, Buzga Marek, Krumpolec Patrik, Skopkova Martina, Surova Martina, Ukropcova Barbara, Ticha Lubica, Petrasova Miroslava, Gabcova Dominika, Huckova Miroslava, Piskorova Lucie, Bozensky Jan, Mokan Marian, Ukropec Jozef, Zavacka Ivona, Klimes Iwar, Stanik Juraj, Gasperikova Daniela
机构信息
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.
出版信息
PLoS One. 2017 May 4;12(5):e0177222. doi: 10.1371/journal.pone.0177222. eCollection 2017.
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.
背景
下丘脑转录因子单 minded1（SIM1）的失活突变已被证明是早发性严重肥胖的一个原因。然而，迄今为止，SIM1 突变对肥胖表型的影响仅在少数人群中进行了研究。在本研究中，我们对斯洛伐克和摩拉维亚血统的严重肥胖儿童的 SIM1 功能区域进行了筛查，以确定 SIM1 内的基因变异是否可能影响这些人群的肥胖发展。
方法
对 126 名无关的肥胖儿童和青少年（2 - 18 岁）以及 41 名斯洛伐克和摩拉维亚血统的成年瘦对照者的 SIM1 启动子区域、外显子和外显子 - 内含子边界进行测序。儿童和青少年的纳入标准是年龄和性别相适应的体重指数标准差得分高于 2 个标准差，且肥胖发病年龄小于 5 岁。将 SIM1 变异携带者的临床表型与 4 名 MC4R 变异携带者以及 27 名年龄和性别匹配的无关 SIM1 和 MC4R 突变阴性肥胖对照者的临床表型进行比较。
结果
鉴定出 7 种先前描述的 SIM1 变异和 1 种新的杂合变异 p.D134N。通过 7 种计算机软件分析预测该新变异具有致病性，且位于 SIM1 蛋白的高度保守位置。p.D134N 变异在一名 18 岁女性先证者（BMI 44.2kg/m²；+7.5 个标准差）以及 3 名肥胖家庭成员中被发现。尽管有早发性严重肥胖，但先证者及其 16 岁的哥哥不符合代谢综合征的标准。此外，与肥胖对照者相比，变异携带者对高糖食物（p = 0.02）和低脂、低碳水化合物、高蛋白食物（p = 0.02）的偏好明显更低。
结论
我们在一个单一谱系的 4 名肥胖个体中鉴定出一种新的 SIM1 变异 p.D134N，其也与对某些食物的较低偏好相关。
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