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New mutations at the imprinted Gnas cluster show gene dosage effects of Gsa in postnatal growth and implicate XLas in bone and fat metabolism, but not in suckling

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posted on 2023-06-08, 07:13 authored by Mark Maconochie, E Sally, W Christine, B Simon, B Colin, M Lee, E Jessica, T Lydia, P Jo
The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLas, XLN1, and ALEX or a double dose of maternally expressed Gsa to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsa, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsa and loss of expression of XLas and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLas, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLas. This is, to our knowledge, the first report describing a role for XLas in bone metabolism. We propose that XLas is involved in the regulation of bone and adipocyte metabolism.

History

Publication status

  • Published

File Version

  • Published version

Journal

Molecular and Cellular Biology

ISSN

1098-5549

Publisher

American Society for Microbiology

Issue

5

Volume

32

Page range

1017-1029

Department affiliated with

  • Neuroscience Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2013-04-26

First Open Access (FOA) Date

2016-03-22

First Compliant Deposit (FCD) Date

2016-08-17

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