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

Autoři: Stefan Bagheri-Fam aff001;  Huijun Chen aff002;  Sean Wilson aff003;  Katie Ayers aff003;  James Hughes aff005;  Frederique Sloan-Bena aff006;  Pierre Calvel aff007;  Gorjana Robevska aff003;  Beatriz Puisac aff008;  Kamila Kusz-Zamelczyk aff009;  Stefania Gimelli aff006;  Anna Spik aff009;  Jadwiga Jaruzelska aff009;  Alina Warenik-Szymankiewicz aff010;  Sultana Faradz aff011;  Serge Nef aff006;  Juan Pié aff008;  Paul Thomas aff005;  Andrew Sinclair aff003;  Dagmar Wilhelm aff001
Působiště autorů: Department of Anatomy & Neuroscience, The University of Melbourne, Melbourne, Australia aff001;  Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia aff002;  Murdoch Children’s Research Institute, Melbourne, Australia aff003;  Department of Paediatrics, The University of Melbourne, Melbourne, Australia aff004;  School of Biological Sciences, University of Adelaide, Adelaide, Australia aff005;  Service of Genetic Medicine, University Geneva Hospitals, Geneva, Switzerland aff006;  Department of Genetics, Medicine & Development, University of Geneva, Geneva, Switzerland aff007;  Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, Zaragoza, Spain aff008;  Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland aff009;  Department of Gynecological Endocrinology Poznan University of Medical Sciences, Poznan, Poland aff010;  Center for Biomedical Research Faculty of Medicine Diponegoro University (FMDU), Semarang, Indonesia aff011
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article


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.

Klíčová slova:

Cell differentiation – Embryos – Gene expression – Germ cells – Gonads – Ovaries – Testes – Sertoli cells


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