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首页> 外文期刊>Journal of the Endocrine Society. >OR33-06 Potential Role of Mutations in TBX3 in Human Weight Regulation
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OR33-06 Potential Role of Mutations in TBX3 in Human Weight Regulation

机译：OR33-06在人体重调节中TBX3中突变在突变的潜在作用

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Introduction: Tbx3 has been shown to play a role in the terminal specification of hypothalamic melanocortin neurons during neonatal development & in maintaining the plasticity of their peptidergic role in adulthood in animal experiments (1). The absence of humans with biallelic mutations in TBX3 & the conservation of the critical domains across species emphasizes its essential role in life. Heterozygous mutations in humans have been associated with ulnar mammary syndrome (UMS) with a spectrum of phenotype including obesity. Based on these observations, we hypothesized that heterozygous mutations in the conserved regions of TBX3 may play an important role in the weight regulation pathway in humans. Methods: The Genetics of Early Childhood Obesity (GECO) study enrolls children with severe (BMI 120% of 95th %tile of CDC reference) early onset (A). The proband is an 11-year old boy with morbid obesity (BMI 43.9 kg/m2, BMIz 3.25), advanced bone age, precocious puberty & type 2 diabetes. Trio analysis ruled out recessive & compound heterozygote causative variants, & none of the identified de novo variants were considered pathogenic. His mother suffers from severe obesity (BMI 38 kg/m2 post-bariatric surgery) supporting an autosomal dominant inheritance of the phenotype. The putative causal variant in TBX3 segregates in the proband, mother & maternal grandmother. Located in the DNA binding domain of T-box, the variant is predicted to be deleterious by 4 in silico algorithms & rare in population-based databases (mean allele frequency 0.006% in gNOMAD, absent in ClinVar). Consistent with the variable penetrance of the phenotype in UMS, neither mother nor child have the classic features, but, the mother has uterine anomalies causing 6 spontaneous abortions & was unable to breast feed due to inverted nipples. Ongoing functional studies in human hypothalamic neurons suggest that a decrease in melanocortin signaling possibly explaining the phenotype in this family. Conclusions: Mutations in TBX3 in humans may have a role as a monogenic cause of obesity and disease-relevant hypothalamic stem cells can serve as models to study them.
机译：简介：TBX3已被证明在新生儿发育期间丘脑敏氨酰素质素神经元的终端规范中发挥作用，并且在动物实验中的成年中的脑卒中作用的可塑性（1）。 TBX3中具有双胞胎突变的人类的缺失和跨物种的关键结构域的守恒强调其在生活中的基本作用。人体中的杂合酶突变与Ulnar乳腺综合征（UMS）有关，具有包括肥胖的谱的谱。基于这些观察结果，我们假设TBX3的保守区域中的杂合子突变可能在人类体重调控途径中起重要作用。方法：早期儿童肥胖症（GECO）研究的遗传学注册严重的儿童（BMI> 120％的CDC参考）早期发作（a）。概念是一个11岁的男孩，病态肥胖症（BMI 43.9 kg / m2，bmiz 3.25），晚期骨骼年龄，早熟青春期和2型糖尿病。三重血分析排除了隐性和复合杂合子的致病变体，没有鉴定的de Novo变体被认为是致病性的。他的母亲患有严重的肥胖症（BMI 38 kg / m2后牛仔术后），支持对表型的常染色体显性遗传。在证据，母亲及外祖母中的TBX3隔离中的推定因果变量。位于T盒的DNA结合结构域中，该变体预计在硅算法中的4个含量为4，群体基于人群数据库（平均等位基因频率为0.006％，在Clinvar中不存在）。与UMS中表型的可变渗透相一致，母亲和孩子都没有经典的特征，但是，母亲有子宫异常，导致6个自发流亡，由于倒乳头而无法母乳喂养。人类下丘脑神经元的持续功能研究表明，Melanocortin信号的减少可能解释这个家庭中的表型。结论：人类TBX3的突变可能具有肥胖的单一原因和疾病相关的下丘脑干细胞的作用可以作为研究它们的模型。

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