The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice

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 Pié; Paul Thomas; Andrew Sinclair; Dagmar Wilhelm

doi:10.1371/journal.pone.0227411

The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice

PLoS One. 2020 Jan 7;15(1):e0227411. doi: 10.1371/journal.pone.0227411. eCollection 2020.

Authors

Stefan Bagheri-Fam¹, Huijun Chen², Sean Wilson³, Katie Ayers^{3

4}, James Hughes⁵, Frederique Sloan-Bena⁶, Pierre Calvel⁷, Gorjana Robevska^{3

4}, Beatriz Puisac⁸, Kamila Kusz-Zamelczyk⁹, Stefania Gimelli⁶, Anna Spik⁹, Jadwiga Jaruzelska⁹, Alina Warenik-Szymankiewicz¹⁰, Sultana Faradz¹¹, Serge Nef⁶, Juan Pié⁸, Paul Thomas⁵, Andrew Sinclair^{3

4}, Dagmar Wilhelm¹

Affiliations

¹ Department of Anatomy & Neuroscience, The University of Melbourne, Melbourne, Australia.
² Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
³ Murdoch Children's Research Institute, Melbourne, Australia.
⁴ Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
⁵ School of Biological Sciences, University of Adelaide, Adelaide, Australia.
⁶ Service of Genetic Medicine, University Geneva Hospitals, Geneva, Switzerland.
⁷ Department of Genetics, Medicine & Development, University of Geneva, Geneva, Switzerland.
⁸ Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, Zaragoza, Spain.
⁹ Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland.
¹⁰ Department of Gynecological Endocrinology Poznan University of Medical Sciences, Poznan, Poland.
¹¹ Center for Biomedical Research Faculty of Medicine Diponegoro University (FMDU), Semarang, Indonesia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Animals
Disorders of Sex Development / genetics*
Disorders of Sex Development / pathology
Female
Gene Expression Regulation, Developmental / genetics
Gonadal Dysgenesis / genetics*
Gonadal Dysgenesis / pathology
Gonads / growth & development*
Gonads / pathology
Heterozygote
Humans
Hydroxymethylglutaryl-CoA Synthase / genetics*
Male
Mice
Mutation, Missense / genetics
Ovary / growth & development
Ovary / pathology
Sertoli Cells / metabolism
Sex-Determining Region Y Protein / genetics
Testis / growth & development
Testis / pathology

Substances

HMGCS2 protein, human
Sex-Determining Region Y Protein
Sry protein, mouse
HMGCS2 protein, mouse
Hydroxymethylglutaryl-CoA Synthase

Grants and funding

This work was supported by an Australian Research Council Future Fellowship [FT110100327] and an Australian Research Council discovery grant [DP170100045] to DW, a National Health & Medical Research Council program grant [APP1074258] to AS, as well as partly funded by Riset Unggulan Univeritas Diponegoro [PNBP no 316-01/UN7.5.1/PG/2015] to SF, the Swiss National Science Foundation [joint research project SCOPES IZ73Z0_152347/1] to SN and JJ and the Diputación General de Aragón [Grupo B32_17R] and European Social Fund [FEDER] to BP and JP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.