Gene Dosage Effects at the Imprinted Gnas Cluster.

Genomic imprinting results in parent-of-origin-dependent monoallelic gene expression. Early work showed that distal mouse chromosome 2 is imprinted, as maternal and paternal duplications of the region (with corresponding paternal and maternal deficiencies) give rise to different anomalous phenotypes...

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Autores principales:	Simon T Ball, Michelle L Kelly, Joan E Robson, Martin D Turner, Jackie Harrison, Lynn Jones, Diane Napper, Colin V Beechey, Tertius Hough, Antonius Plagge, Bruce M Cattanach, Roger D Cox, Jo Peters
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7f4c01aa4f9a401192e8b77cad145176
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spelling	oai:doaj.org-article:7f4c01aa4f9a401192e8b77cad1451762021-11-18T07:41:30ZGene Dosage Effects at the Imprinted Gnas Cluster.1932-620310.1371/journal.pone.0065639https://doaj.org/article/7f4c01aa4f9a401192e8b77cad1451762013-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0065639https://doaj.org/toc/1932-6203Genomic imprinting results in parent-of-origin-dependent monoallelic gene expression. Early work showed that distal mouse chromosome 2 is imprinted, as maternal and paternal duplications of the region (with corresponding paternal and maternal deficiencies) give rise to different anomalous phenotypes with early postnatal lethalities. Newborns with maternal duplication (MatDp(dist2)) are long, thin and hypoactive whereas those with paternal duplication (PatDp(dist2)) are chunky, oedematous, and hyperactive. Here we focus on PatDp(dist2). Loss of expression of the maternally expressed Gnas transcript at the Gnas cluster has been thought to account for the PatDp(dist2) phenotype. But PatDp(dist2) also have two expressed doses of the paternally expressed Gnasxl transcript. Through the use of targeted mutations, we have generated PatDp(dist2) mice predicted to have 1 or 2 expressed doses of Gnasxl, and 0, 1 or 2 expressed doses of Gnas. We confirm that oedema is due to lack of expression of imprinted Gnas alone. We show that it is the combination of a double dose of Gnasxl, with no dose of imprinted Gnas, that gives rise to the characteristic hyperactive, chunky, oedematous, lethal PatDp(dist2) phenotype, which is also hypoglycaemic. However PatDp(dist2) mice in which the dosage of the Gnasxl and Gnas is balanced (either 2∶2 or 1∶1) are neither dysmorphic nor hyperactive, have normal glucose levels, and are fully viable. But PatDp(dist2) with biallelic expression of both Gnasxl and Gnas show a marked postnatal growth retardation. Our results show that most of the PatDp(dist2) phenotype is due to overexpression of Gnasxl combined with loss of expression of Gnas, and suggest that Gnasxl and Gnas may act antagonistically in a number of tissues and to cause a wide range of phenotypic effects. It can be concluded that monoallelic expression of both Gnasxl and Gnas is a requirement for normal postnatal growth and development.Simon T BallMichelle L KellyJoan E RobsonMartin D TurnerJackie HarrisonLynn JonesDiane NapperColin V BeecheyTertius HoughAntonius PlaggeBruce M CattanachRoger D CoxJo PetersPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e65639 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Simon T Ball Michelle L Kelly Joan E Robson Martin D Turner Jackie Harrison Lynn Jones Diane Napper Colin V Beechey Tertius Hough Antonius Plagge Bruce M Cattanach Roger D Cox Jo Peters Gene Dosage Effects at the Imprinted Gnas Cluster.
description	Genomic imprinting results in parent-of-origin-dependent monoallelic gene expression. Early work showed that distal mouse chromosome 2 is imprinted, as maternal and paternal duplications of the region (with corresponding paternal and maternal deficiencies) give rise to different anomalous phenotypes with early postnatal lethalities. Newborns with maternal duplication (MatDp(dist2)) are long, thin and hypoactive whereas those with paternal duplication (PatDp(dist2)) are chunky, oedematous, and hyperactive. Here we focus on PatDp(dist2). Loss of expression of the maternally expressed Gnas transcript at the Gnas cluster has been thought to account for the PatDp(dist2) phenotype. But PatDp(dist2) also have two expressed doses of the paternally expressed Gnasxl transcript. Through the use of targeted mutations, we have generated PatDp(dist2) mice predicted to have 1 or 2 expressed doses of Gnasxl, and 0, 1 or 2 expressed doses of Gnas. We confirm that oedema is due to lack of expression of imprinted Gnas alone. We show that it is the combination of a double dose of Gnasxl, with no dose of imprinted Gnas, that gives rise to the characteristic hyperactive, chunky, oedematous, lethal PatDp(dist2) phenotype, which is also hypoglycaemic. However PatDp(dist2) mice in which the dosage of the Gnasxl and Gnas is balanced (either 2∶2 or 1∶1) are neither dysmorphic nor hyperactive, have normal glucose levels, and are fully viable. But PatDp(dist2) with biallelic expression of both Gnasxl and Gnas show a marked postnatal growth retardation. Our results show that most of the PatDp(dist2) phenotype is due to overexpression of Gnasxl combined with loss of expression of Gnas, and suggest that Gnasxl and Gnas may act antagonistically in a number of tissues and to cause a wide range of phenotypic effects. It can be concluded that monoallelic expression of both Gnasxl and Gnas is a requirement for normal postnatal growth and development.
format	article
author	Simon T Ball Michelle L Kelly Joan E Robson Martin D Turner Jackie Harrison Lynn Jones Diane Napper Colin V Beechey Tertius Hough Antonius Plagge Bruce M Cattanach Roger D Cox Jo Peters
author_facet	Simon T Ball Michelle L Kelly Joan E Robson Martin D Turner Jackie Harrison Lynn Jones Diane Napper Colin V Beechey Tertius Hough Antonius Plagge Bruce M Cattanach Roger D Cox Jo Peters
author_sort	Simon T Ball
title	Gene Dosage Effects at the Imprinted Gnas Cluster.
title_short	Gene Dosage Effects at the Imprinted Gnas Cluster.
title_full	Gene Dosage Effects at the Imprinted Gnas Cluster.
title_fullStr	Gene Dosage Effects at the Imprinted Gnas Cluster.
title_full_unstemmed	Gene Dosage Effects at the Imprinted Gnas Cluster.
title_sort	gene dosage effects at the imprinted gnas cluster.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/7f4c01aa4f9a401192e8b77cad145176
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_version_	1718423107640754176

Gene Dosage Effects at the Imprinted Gnas Cluster.

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