Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity.

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 thatTrappc9, a cellular trafficking factor, was expressed predominantly (similar to 70%) from the maternally inherited allele. Loss-of-function mutations in human TRAPPC9 cause a rare neurodevelopmental syndrome characterized by microcephaly and obesity. By studyingTrappc9null 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 forTrappc9in energy balance was further supported by increasedad libitumfood 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 thatTrappc9deficient mice recapitulate key pathological features ofTRAPPC9mutations in humans and identify a role forTrappc9and its imprinting in controlling brain development and metabolism. Author summary Every person has inherited two copies of each gene, one from each parent. In most cases two copies contribute equally. Other genes may express only from one parental copy, or express both copies but prefer one over another, a phenomenon called genomic imprinting. Here we first investigated the expression bias between two parental copies in the brain, then focused on one gene with maternal biased expression calledTrappc9. Mutations in human TRAPPC9 cause a neurodevelopmental disorder marked by smaller brain size and increased body weight. Indeed, we found mice lacking ofTrappc9showed a reduction in brain size, behavioral changes and a marked increase in body weight. A functional role forTrappc9in metabolism was further supported by increased food intake in a child lacking this gene. Interestingly, we also found mice lacking the preferred copy (from mother) of the gene showed similar disorders, whereas mice lacking the other copy (from father) appeared normal. We provide an animal model of a rare genetic disease and identify a role forTrappc9and its imprinting in controlling brain development and metabolism.