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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.

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