Pathophysiological mechanism
The NR5A1 mutations identified in DSD-related conditions cause a loss of function of this gene, meaning that the gene will be less active.
NR5A1 is a so-called nuclear receptor (NR). To function, a receptor usually needs to bind a ligand. This mechanism is comparable to the key you need to unlock the door. In this metaphor, the ligand is the key and the receptor is the door lock. However, a bit oddly, for NR5A1, there is no known ligand, making it an orphan receptor.
Nuclear receptors, and thus NR5A1 as well, are transcription factors (TFs). These transcription factors are important for regulating which genes will become active in which cell types. After all, our DNA is the same in all our cells, yet the cells in our skin are completely different from those in our brain or our gonads. These differences are caused by differences in gene activity (= gene expression). For instance, a gene important in gonadal cells will not be expressed in the cell of our skin and vice versa. Transcription factors, like NR5A1, bind these genes and function as a light switch for expression. When the TF doesn’t work properly, the expression of target genes will be lowered. On the other hand, when a TF works to well, it might activate genes that shouldn’t be activated in a certain cell type, also an unfavourable situation. These mechanisms are extremely important during development, as during development the different types of cells are formed, and all of our tissues and organs differentiate. This also explains why small mistakes in NR5A1 can result in atypical adrenal and gonadal development. Depending on the type of error, one condition or another can arise.
Genotype-phenotype correlations
For some genes we know exactly which genetic error results in which condition, we call that genotype-phenotype correlations. However, for NR5A1 mutations we don’t know precisely, yet there are some trends.
- 46,XY DSD and primary adrenal insufficiency (PAI)
To date only two specific NR5A1 variants have been found in patients with 46,XY DSD and PAI. One of them inherits dominantly, which means that it’s sufficient to have one defect copy of the gene to develop a phenotype, the other one inherits recessively, meaning that you need 2 defect copies. Both mutations disable NR5A1 from correctly activating NR5A1 target genes.
- Isolated 46,XY DSD
Mutations associated with 46,XY DSD without PAI are spread over the entire gene. These heterozygous mutations (there is only one copy of the defect) are usually de novo, meaning that the defect is not present in either of the parents. However approximately one third of mutations are maternally inherited. Women carrying these mutations are at risk for developing POI. Furthermore, few cases of paternal transmission have been described, these men usually have a history of hypospadias but appear to have preserved fertility. This clearly shows that the conditions associated with NR5A1 variation have incomplete penetrance, meaning that not all people carrying the mutation will have a problem. In general, it is estimated the approximately 15% of 46,XY DSD cases can be explained by underlying NR5A1 mutations.
- 46,XX DSD
Currently, only three different NR5A1 mutations have been associated with 46,XX DSD and remarkably one of these variants can also cause 46,XY DSD.
Diagnostic testing
- Genetic testing
NR5A1 sequencing or whole exome sequencing: here we sequence all the genes in our DNA.
Copy number assessment: usually we have two copies of each gene (one from our mother, the other one from our father), however loss of one of these copies can result in a (developmental) disorder.
- Biochemical analyses
Measurements of androgen precursors, and other hormones produced by the testis (AMH, Inhibin B). (Dihydro)testosterone, gonadotropin levels.