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

Document Type

Article

Publication Date

9-2-2020

Keywords

JMG, Animals, Child, Female, Gene Expression Regulation, Gene Frequency, Genomic Imprinting, Heterozygote, Homozygote, Humans, Intercellular Signaling Peptides and Proteins, Male, Maternal Inheritance, Mice, Mice, Inbred C57BL, Mice, Knockout, Microcephaly, Mutation, Obesity, Phenotype

JAX Source

PLoS Genet 2020 Sep 2; 16(9):e1008916

Volume

16

Issue

9

First Page

1008916

Last Page

1008916

ISSN

1553-7404

PMID

32877400

DOI

https://doi.org/10.1371/journal.pgen.1008916

Abstract

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.

Comments

This is an open access article distributed under the terms of the Creative Commons Attribution License.

Please contact the Joan Staats Library for information regarding this document.

Share

COinS