Some imprinted genes exhibit parental origin specific expression bias rather than being transcribed exclusively from one copy. The physiological relevance of this remains poorly understood. In an analysis of brain-specific allele-biased expression, we identified that Trappc9, a cellular trafficking factor, was expressed predominantly (~70%) from the maternally inherited allele. Loss-of-function mutations in human TRAPPC9 cause a rare neurodevelopmental syndrome characterized by microcephaly and obesity. By studying Trappc9 null mice we discovered that homozygous mutant mice showed a reduction in brain size, exploratory activity and social memory, as well as a marked increase in body weight. A role for Trappc9 in energy balance was further supported by increased ad libitum food intake in a child with TRAPPC9 deficiency. Strikingly, heterozygous mice lacking the maternal allele (70% reduced expression) had pathology similar to homozygous mutants, whereas mice lacking the paternal allele (30% reduction) were phenotypically normal. Taken together, we conclude that Trappc9 deficient mice recapitulate key pathological features of TRAPPC9 mutations in humans and identify a role for Trappc9 and its imprinting in controlling brain development and metabolism.

一些印记基因表现出亲本起源特异性表达偏差，而不是仅从一个拷贝转录。其生理相关性仍知之甚少。在对大脑特异性等位基因偏向表达的分析中，我们发现Trappc9（一种细胞运输因子）主要（约 70%）由母系遗传的等位基因表达。人类 TRAPPC9 的功能丧失突变会导致一种罕见的神经发育综合征，其特征是小头畸形和肥胖。通过研究Trappc9缺失小鼠，我们发现纯合突变小鼠的大脑尺寸、探索活动和社会记忆均有所减少，并且体重显着增加。TRAPPC9 缺陷儿童的随意食物摄入量增加进一步支持了Trappc9在能量平衡中的作用。引人注目的是，缺乏母源等位基因（表达减少 70%）的杂合小鼠具有与纯合突变体相似的病理学，而缺乏父源等位基因（表达减少 30%）的小鼠表型正常。综上所述，我们得出结论，Trappc9缺陷小鼠重现了人类TRAPPC9突变的关键病理特征，并确定了Trappc9及其印记在控制大脑发育和代谢中的作用。