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

Bagheri-Fam, Stefan
Chen, Huijun
Wilson, Sean
Ayers, Katie
Hughes, James
Robevska, Gorjana
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Published in PloS one. 2020, vol. 15, no. 1, e0227411
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 AdolescentAnimalsDisorders of Sex Development/genetics/pathologyFemaleGene Expression RegulationDevelopmental/geneticsGonadal Dysgenesis/genetics/pathologyGonads/growth & development/pathologyHeterozygoteHumansHydroxymethylglutaryl-CoA Synthase/geneticsMaleMiceMutationMissense/geneticsOvary/growth & development/pathologySertoli Cells/metabolismSex-Determining Region Y Protein/geneticsTestis/growth & development/pathology
PMID: 31910233
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Article (Published version) (4.9 MB) - public document Free access
Research group Mécanismes moléculaires et génétiques du développement sexuel (778)
Swiss National Science Foundation: SCOPES IZ73Z0_152347/1
(ISO format)
BAGHERI-FAM, Stefan et al. The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice. In: PLOS ONE, 2020, vol. 15, n° 1, p. e0227411. doi: 10.1371/journal.pone.0227411 https://archive-ouverte.unige.ch/unige:139078

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Deposited on : 2020-08-06

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