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 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.


PLoS Genet


PLoS genetics


Liang ZS,Cimino I,Yalcin B,Raghupathy N,Vancollie VE,Ibarra-Soria X,Firth HV,Rimmington D,Farooqi IS,Lelliott CJ,Munger SC,O'Rahilly S,Ferguson-Smith AC,Coll AP,Logan DW




Has Abstract


2020-09-02 00:00:00














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