Scientific article
Open access

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

Published inPLOS ONE, vol. 15, no. 1, e0227411
Publication date2020

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.

  • Adolescent
  • Animals
  • Disorders of Sex Development/genetics/pathology
  • Female
  • Gene Expression Regulation
  • Developmental/genetics
  • Gonadal Dysgenesis/genetics/pathology
  • Gonads/growth & development/pathology
  • Heterozygote
  • Humans
  • Hydroxymethylglutaryl-CoA Synthase/genetics
  • Male
  • Mice
  • Mutation
  • Missense/genetics
  • Ovary/growth & development/pathology
  • Sertoli Cells/metabolism
  • Sex-Determining Region Y Protein/genetics
  • Testis/growth & development/pathology
  • Swiss National Science Foundation - SCOPES IZ73Z0_152347/1
Citation (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
Main files (1)
Article (Published version)
ISSN of the journal1932-6203

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