The sexual development of an embryo does not depend on a single instruction, but on a chain of signals that must fire in the right order and the right place. When one link in that chain fails, development can take a different path from the one the chromosomes seemed to dictate. A research team has now identified a specific variant of the NR5A1 gene able to derail that process, and has described for the first time what happens inside the cell when it appears. The work is published in the journal Genes.
The NR5A1 gene builds a protein that works as a master switch: it turns other genes involved in the formation of the gonads and the adrenal glands on and off. Its faults have been linked for years to disorders or differences of sex development (DSD), a broad group of conditions in which the chromosomal, gonadal and anatomical sex do not follow the most common route. In 46,XY individuals this can mean incomplete masculinization, gonads that fail to mature as expected, or remnants of embryonic structures that would normally disappear.
The authors studied two patients with DSD and found the same variant in both: a single letter change in the DNA, position 88 (c.88T>A), which swaps the amino acid cysteine for serine in the protein (p.Cys30Ser). Two unrelated people sharing exactly that alteration, in such a large gene, is unusual and suggests that this particular spot matters functionally.
To check that, they went beyond a genetic description. Using immunofluorescence they tracked where the protein sits inside the cell and saw a clear difference: the normal version concentrates in the nucleus, where it must be to regulate DNA, while the mutated version was split between the nucleus and the cytoplasm. Less protein in the nucleus means less power to issue orders to genes.
The remaining tests traced the consequences of that displacement. RNA sequencing showed the variant alters the expression of 642 genes, and the deregulated ones cluster mainly in the neuroactive ligand-receptor interaction pathway, a chemical communication network linking the nervous and endocrine systems. Transactivation of the usual NR5A1 targets was impaired and, as a result, 560 genes were expressed far below normal. Among the most affected are KISS1R, CYP11A1, STAR, GABRP and GRAMD1D: key pieces of the hormonal axis that starts in the brain, tells the gonad to produce sex hormones and sustains pubertal development.
The finding has a direct clinical reading. In many cases of DSD in 46,XY children the cause is never identified, and having variants characterized at the functional level — not merely detected — helps tell apart which DNA changes truly explain the picture and which are harmless variants. The authors also suggest that gene expression studies in peripheral blood, using samples that are easy to obtain, can provide clues when the genetic diagnosis falls short.
Expectations should stay measured. This is two patients and laboratory work: it establishes a mechanism, not a therapy or a prediction rule. Nor does it say anything about the gender identity of people with DSD, which is a different question from anatomical and hormonal development. What it does offer is one more piece of a map medicine needs: understanding how biological sex is built, in order to support with information and without dogmas those born with an atypical sex development and those receiving gender-affirming care.
Source: Identification and Functional Characteristics of NR5A1 Gene Variant in Patients with 46,XY Disorders of Sex Development. He Y, Li X, Li Y, Sun Y, Zheng X, Chu Y, Chen X, Li J. Genes 2026;17(9):1070. DOI: 10.3390/genes17091070.
Article published on dosier.es. Image generated with artificial intelligence (marta ai → marta.syf.es).
