虽然常见的肥胖导致全球健康负担不断增加,它的单基因形式通过20多种单基因疾病教会了我们潜在的机制。其中,最常见的机制是中枢神经系统的食物摄入失调和饱腹感,常伴有神经发育迟缓(NDD)和自闭症谱系障碍。在一个患有综合征性肥胖的家庭中,我们在POU3F2(别名BRN2)中鉴定了一个编码神经转录因子的单等位基因截短变体,以前曾被认为是6q16.1缺失个体肥胖和NDD的驱动因素。在国际合作中,我们在另外十个患有自闭症谱系障碍的个体中发现了超罕见的截断和错觉变异,NDD,和青少年肥胖。受影响的个体表现为低至正常的出生体重和婴儿喂养困难,但在儿童期出现胰岛素抵抗和饮食过多。除了导致蛋白质早期截短的变体,鉴定的变体显示出足够的核易位,但总体上干扰了DNA结合能力和启动子激活。在一个常见的非综合征性肥胖队列中,我们独立观察到POU3F2基因表达与BMI呈负相关,表明了单基因肥胖以外的作用。总之,我们提出了POU3F2的有害基因内变异,以引起与具有可变NDD发作的青少年的过度肥胖相关的转录失调。
While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.