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

• DOI: 10.1371/journal.pone.0227411
• Publication Date: 2020-01-07T18:42:00Z
• Authors: Stefan Bagheri-Fam; Huijun Chen; Sean Wilson; Katie Ayers; James Hughes; Frederique Sloan-...; Pierre Calvel; Gorjana Robevska; Beatriz Puisac; Kamila Kusz-Zamel...; Stefania Gimelli; Anna Spik; Jadwiga Jaruzelska; Alina Warenik-Szy...; Sultana Faradz; Serge Nef; Juan Pié; Paul Thomas; Andrew Sinclair; Dagmar Wilhelm
• Keywords: Testis determining factor; Gonadal dysgenesis

Disorders/differences of sex development (DSD) cause profound psychological and reproductive consequences for the affected individuals, however, most are still unexplained at molecular level. Here, we present a novel gene, 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (HMGCS2), encoding metabolic enzyme in liver important energy production from fatty acids, that shows an unusual expression pattern developing fetal mouse gonads. Shortly after gonadal determination it is up-regulated testes following very similar spatial temporal as male-determining gene Sry Sertoli cells before switching to ovarian enriched expression. To test if Hmgcs2 gonad mammals, pursued two lines investigations. Firstly, generated Hmgcs2-null mice using CRISPR/Cas9 found these had gonads developed normally even on sensitized background. Secondly, screened 46,XY DSD patients with dysgenesis identified unrelated deletion deleterious missense variant HMGCS2 respectively. However, both variants were heterozygous, suggesting might not be causative gene. Analysis larger number future shed more light into possible association human development.