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

• DOI: 10.1371/journal.pgen.1008916
• Publication Date: 2020-09-02T17:22:42Z
• Authors: Zhengzheng S. Liang; Irene Cimino; Binnaz Yalcin; Narayanan Raghupathy; Valerie E. Vancollie; Ximena Ibarra-Soria; Helen V. Firth; Debra Rimmington; I. Sadaf Farooqi; Christopher J. Le...; Steven C. Munger; Stephen O’Rahilly; Anne C. Ferguson-...; Anthony P. Coll; Darren W. Logan
• Keywords: Microcephaly; Genomic Imprinting; Imprinting (psychology); Null allele

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