Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/132691
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Type: | Journal article |
Title: | The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice |
Author: | Bagheri-Fam, S. Chen, H. Wilson, S. Ayers, K. Hughes, J. Sloan-Bena, F. Calvel, P. Robevska, G. Puisac, B. Kusz-Zamelczyk, K. Gimelli, S. Spik, A. Jaruzelska, J. Warenik-Szymankiewicz, A. Faradz, S. Nef, S. Pié, J. Thomas, P. Sinclair, A. Wilhelm, D. |
Citation: | PLoS One, 2020; 15(1):1-23 |
Publisher: | Public Library of Science |
Issue Date: | 2020 |
ISSN: | 1932-6203 1932-6203 |
Editor: | Yenugu, S. |
Statement of Responsibility: | Stefan Bagheri-Fam, Huijun Chen, Sean Wilson, Katie Ayers, James Hughes, Frederique Sloan-Bena, Pierre Calvel, Gorjana Robevska, Beatriz Puisac, Kamila Kusz-Zamelczyk, Stefania Gimelli, Anna Spik, Jadwiga Jaruzelska, Alina Warenik-Szymankiewicz, Sultana Faradz, Serge Nef, Juan Pie, Paul Thomas, Andrew Sinclair, Dagmar Wilhelm |
Abstract: | Disorders/differences of sex development (DSD) cause profound psychological and reproductive consequences for the affected individuals, however, most are still unexplained at the molecular level. Here, we present a novel gene, 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (HMGCS2), encoding a metabolic enzyme in the liver important for energy production from fatty acids, that shows an unusual expression pattern in developing fetal mouse gonads. Shortly after gonadal sex determination it is up-regulated in the developing testes following a very similar spatial and temporal pattern as the male-determining gene Sry in Sertoli cells before switching to ovarian enriched expression. To test if Hmgcs2 is important for gonad development in mammals, we pursued two lines of investigations. Firstly, we generated Hmgcs2-null mice using CRISPR/Cas9 and found that these mice had gonads that developed normally even on a sensitized background. Secondly, we screened 46,XY DSD patients with gonadal dysgenesis and identified two unrelated patients with a deletion and a deleterious missense variant in HMGCS2 respectively. However, both variants were heterozygous, suggesting that HMGCS2 might not be the causative gene. Analysis of a larger number of patients in the future might shed more light into the possible association of HMGCS2 with human gonadal development. |
Keywords: | Ovary Testis Sertoli Cells Gonads Animals Humans Mice Gonadal Dysgenesis Hydroxymethylglutaryl-CoA Synthase Gene Expression Regulation, Developmental Heterozygote Mutation, Missense Adolescent Female Male Sex-Determining Region Y Protein Disorders of Sex Development |
Rights: | © 2020 Bagheri-Fam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
DOI: | 10.1371/journal.pone.0227411 |
Grant ID: | http://purl.org/au-research/grants/arc/FT110100327 http://purl.org/au-research/grants/arc/DP170100045 http://purl.org/au-research/grants/nhmrc/APP1074258 |
Published version: | http://dx.doi.org/10.1371/journal.pone.0227411 |
Appears in Collections: | Biochemistry publications |
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hdl_132691.pdf | Published version | 5.02 MB | Adobe PDF | View/Open |
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