Disorders of sex development (DSD) include all congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical. They occur in approximately 1 in 4,500 live births and represent a major health care burden with profound psychological and reproductive consequences for the patient, as well as increased risk for testicular or ovarian cancer later in life. Despite an increasing knowledge of the genes involved in proper development of the male and female phenotype, most of these disorders are still unexplained at the molecular level.
Here, we present a novel DSD candidate gene, HMGCS2, encoding mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase 2, a metabolic enzyme important for energy production from fatty acids. Mutations in human HMGCS2 are known to cause HMG-CoA synthase-2 deficiency, a very rare autosomal recessive metabolic disorder. We have now identified the first HMGCS2 mutations in two unrelated 46,XY DSD patients with gonadal dysgenesis (disruption of testis differentiation) and male-to-female sex reversal. Patient 1 carries a heterozygous deletion of approximately 20kb at the HMGCS2 locus that removes at least exons 2 to 5 of the HMGCS2 gene, while patient 2 has a heterozygous missense mutation (p.R501P (c.1502G>C)). p.R501P is predicted to disrupt protein structure and displays a complete lack of enzymatic activity in an in vitro enzymatic assay. Gene and protein expression analysis in the mouse testis revealed that Hmgcs2/HMGCS2 is expressed in the ‘sex-determining’ supporting cell lineage (i.e. Sertoli cells). In addition, using the CRISPR genome editing technology, we have generated a Hmgcs2-null mouse model that displays male-to-female gonadal sex reversal. These data strongly implicate HMGCS2 in DSDs and might for the first time shed light on the interplay between metabolism and sex development.