DSDs: genetics, underlying pathologies and psychosexual differentiation

Abstract

Mammalian sex determination is the unique process whereby a single organ, the bipotential gonad, undergoes a developmental switch that promotes its differentiation into either a testis or an ovary. Disruptions of this complex genetic process during human development can manifest as disorders of sex development (DSDs). Sex development can be divided into two distinct processes: sex determination, in which the bipotential gonads form either testes or ovaries, and sex differentiation, in which the fully formed testes or ovaries secrete local and hormonal factors to drive differentiation of internal and external genitals, as well as extragonadal tissues such as the brain. DSDs can arise from a number of genetic lesions, which manifest as a spectrum of gonadal (gonadal dysgenesis to ovotestis) and genital (mild hypospadias or clitoromegaly to ambiguous genitalia) phenotypes. The physical attributes and medical implications associated with DSDs confront families of affected newborns with decisions, such as gender of rearing or genital surgery, and additional concerns, such as uncertainty over the child's psychosexual development and personal wishes later in life. In this Review, we discuss the underlying genetics of human sex determination and focus on emerging data, genetic classification of DSDs and other considerations that surround gender development and identity in individuals with DSDs.

Figure 1

Genetic pathophysiology of human sex determination. Within the developing gonad, regulation of gene transcription occurs through cellular signalling pathways (WNT4–RSPO1 in ovary determination, Map-kinase in testis determination) that activate genes through alteration of chromatin structures and modulation of epigenetic factors or by direct activation of transcriptional networks. In 46,XX individuals, WNT4 and RSPO1 act through Frizzled or LRP5–LRP6 receptors to activate β-catenin (CTNNB1) transcription. β-catenin and FOXL2 promote expression of ovary-specific genes while inhibiting the expression of testis factors such as SOX9. In 46,XY individuals, Map-kinase signalling through MAP3K1 may alter chromatin conformation indirectly through histone modifications (dotted arrow). Map-kinase signalling also increases phosphorylation of transcription factors such as GATA4, which is thought to alter chromatin (dotted arrow) upstream of SRY, and was shown to directly bind to SRY promoter (solid arrow) to activate transcription. Within the nucleus, transcription factors GATA4 and ZFPM2 bind and transactivate SRY and SOX9. Other important factors are CBX2 that has been shown to directly bind the SRY promoter and that, in conjunction with the NR5A1 protein, binds to the SOX9 promoter. The SRY protein can then turn on downstream genes such as SOX9, which initiates the testis gene expression network and represses ovarian-specific genes such as RSPO1 and β-catenin. Ovary-promoting transcription factors are noted in orange and testis-promoting factors are noted in green. Abbreviations: ORF, open reading frame; P, phosphate.