Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity.
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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.
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1553-7404
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Wellcome Trust (207462/Z/17/Z)
Medical Research Council (MR/J001597/1)
Wellcome Trust (095606/Z/11/Z)
Medical Research Council (MR/R009791/1)
MRC (MC_UU_00014/1)
MRC (MC_UU_00014/5)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_12012)