NR5A1 – 46,XY Partial Gonadal Dysgenesis

Steroidogenic factor-1 (SF-1), encoded by NR5A1, is a key nuclear receptor regulating adrenal and gonadal development. Heterozygous loss-of-function variants in SF-1 have been implicated in a spectrum of disorders of sex development (DSD). Here, we summarize the evidence linking SF-1 deficiency to 46,XY partial gonadal dysgenesis (MONDO:0016674).

Genetic Evidence

Autosomal dominant haploinsufficiency of SF-1 underlies 46,XY partial gonadal dysgenesis. In a cohort of 3 unrelated patients, three novel heterozygous SF-1 variants—p.Lys38Ter and p.Leu80TrpfsTer8 introducing premature stop codons in the DNA-binding domain, and an intronic splice-donor change c.1138+1G>T—were identified by exon and boundary sequencing, each predicted to abolish normal SF-1 function and trigger nonsense-mediated decay (PMID:27463801). A subsequent longitudinal study of 33 individuals with 46,XY partial gonadal dysgenesis detected NR5A1 variants in 6 patients (18%), establishing SF-1 defects as the most prevalent molecular cause in this cohort (PMID:29668062). Together, nine unrelated probands support a strong gene–disease association.

Variant Spectrum & Inheritance

Variants include truncating alleles within the zinc-finger domain (e.g., p.Lys38Ter), frameshift mutations (p.Leu80TrpfsTer8), and splice-site defects (c.1138+1G>T), all acting through loss of SF-1 activity. The pattern of heterozygous inheritance with variable expressivity and preserved adrenal function is consistent with an autosomal dominant, sex-limited haploinsufficiency mechanism.

Functional Evidence

In silico splice-site prediction tools confirm aberrant exon skipping for c.1138+1G>T, and experimental models demonstrate SF-1 dosage sensitivity in gonadal development. Murine SF-1 knockout and heterozygous models recapitulate gonadal dysgenesis, corroborating haploinsufficiency as the pathogenic mechanism.

Clinical Utility & Take-Home

Recognition of SF-1 haploinsufficiency in 46,XY partial gonadal dysgenesis informs genetic testing and management, including endocrine evaluation and tailored surveillance. NR5A1 sequencing is recommended for individuals with partial gonadal dysgenesis, even in the presence of spontaneous puberty and normal adrenal function.

References

• Sexual Development • 2016 • NR5A1 Loss‐of‐Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations. PMID:27463801
• Clinical Endocrinology • 2018 • Long-term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis. PMID:29668062

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