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...
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2020-09-01
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Series: | PLoS Genetics |
Online Access: | https://doi.org/10.1371/journal.pgen.1008916 |
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doaj-d7e4936735004c35b3e6c52483f730c42021-06-19T04:31:23ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042020-09-01169e100891610.1371/journal.pgen.1008916Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity.Zhengzheng S LiangIrene CiminoBinnaz YalcinNarayanan RaghupathyValerie E VancollieXimena Ibarra-SoriaHelen V FirthDebra RimmingtonI Sadaf FarooqiChristopher J LelliottSteven C MungerStephen O'RahillyAnne C Ferguson-SmithAnthony P CollDarren W LoganSome 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.https://doi.org/10.1371/journal.pgen.1008916 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 Lelliott Steven C Munger Stephen O'Rahilly Anne C Ferguson-Smith Anthony P Coll Darren W Logan |
spellingShingle |
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 Lelliott Steven C Munger Stephen O'Rahilly Anne C Ferguson-Smith Anthony P Coll Darren W Logan Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. PLoS Genetics |
author_facet |
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 Lelliott Steven C Munger Stephen O'Rahilly Anne C Ferguson-Smith Anthony P Coll Darren W Logan |
author_sort |
Zhengzheng S Liang |
title |
Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. |
title_short |
Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. |
title_full |
Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. |
title_fullStr |
Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. |
title_full_unstemmed |
Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. |
title_sort |
trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2020-09-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pgen.1008916 |
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