Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability
Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability
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DOI：
10.1016/j.ajhg.2015.12.014
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发表时间：
2016-02-04
影响因子：
9.8
通讯作者：
Banka, Siddharth
中科院分区：
文献类型：
--
作者：
Kasher, Paul R.;Schertz, Katherine E.;Banka, Siddharth
智力残疾的遗传学研究和人类肥胖的单基因原因的鉴定为理解大脑和控制体重做出了巨大贡献。瘦素>黑皮质素> SIM 1通路在多种单基因人类肥胖综合征中失调，但其下游靶点仍然未知。在来自六个家庭的十名具有重叠6q16.1缺失的个体中，我们描述了一种具有不同发育迟缓、智力残疾以及对肥胖和食欲过盛易感性的疾病。6q16.1缺失与多重家族中的表型分离，并在四个家族中被证明是从头开始的，并且在独立确定的受影响个体中存在显着的表型重叠，而不存在临床特征的偏倚。对缺失的分析揭示了染色体6q16.1上类似于350 kb的关键区域，该区域包含前神经元转录因子POU 3F 2的基因，该基因对下丘脑的发育和功能很重要。使用吗啉代和突变的斑马鱼模型，我们表明POU 3F 2位于SIM 1的下游，并控制下丘脑神经内分泌视前区的催产素表达。我们发现这一发现与POU 3F 2和相关基因在人脑中的表达模式一致。我们的工作有助于进一步描述能量平衡/体重的神经内分泌控制，并证明这种分子途径在多个物种中是保守的。
Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a similar to 350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstreamof SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.