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

Autoři: Zhengzheng S. Liang aff001;  Irene Cimino aff002;  Binnaz Yalcin aff003;  Narayanan Raghupathy aff004;  Valerie E. Vancollie aff001;  Ximena Ibarra-Soria aff005;  Helen V. Firth aff006;  Debra Rimmington aff002;  I. Sadaf Farooqi aff007;  Christopher J. Lelliott aff001;  Steven C. Munger aff004;  Stephen O’Rahilly aff002;  Anne C. Ferguson-Smith aff008;  Anthony P. Coll aff002;  Darren W. Logan aff001
Působiště autorů: Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom aff001;  MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom aff002;  Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, France aff003;  The Jackson Laboratory, Bar Harbor, Maine, United States of America aff004;  Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom aff005;  Department of Clinical Genetics, Addenbrooke’s Hospital, Cambridge, United Kingdom aff006;  University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, United Kingdom aff007;  Department of Genetics, University of Cambridge, Cambridge, United Kingdom aff008
Vyšlo v časopise: Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. PLoS Genet 16(9): e1008916. doi:10.1371/journal.pgen.1008916
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008916


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.

Klíčová slova:

Animal sociality – Body weight – Gene expression – Genetically modified animals – Heterozygosity – Homozygosity – Mice – Mouse models


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