| Full text | |
| Author(s): |
van den Bergen, Jocelyn
;
Robevska, Gorjana
;
Ferreira, Lucas G. A.
;
Ferreira, Karen R.
;
Kizys, Marina M. L.
;
da Silva, Magnus R. Dias
;
Bruggenwirth, Hennie T.
;
van Bever, Yolande
;
Sinclair, Andrew H.
;
Ayers, Katie L.
Total Authors: 10
|
| Document type: | Journal article |
| Source: | Molecular and Cellular Endocrinology; v. 598, p. 9-pg., 2025-01-11. |
| Abstract | |
In mammals, male sexual development is initiated by the expression of the Sex-determining-Region-Y (SRY) gene. SRY contains a highly conserved high mobility group (HMG) box essential for DNA binding and activity. Variants in SRY cause Differences of Sex Development (DSD), accounting for 10-15% of 46, XY gonadal dysgenesis cases. Here, we present the functional analysis of five SRY coding variants identified in patients with 46, XY DSD. Four variants (p.Asp58Glu, p.Arg75Lys, p.Met85Thr, and p.Arg86Ter) are located within the HMG box and one variant (p.Tyr198Cysfs*18) located in the C-terminal domain. We functionally characterise the impact of these variants in vitro, investigating SRY localisation and transactivational activity using SOX9 regulatory elements that are responsive to SRY. We find that three variants (p.Met85Thr, p.Arg86Ter, and p.Tyr198Cysfs*18) have reduced or abolished transactivational activity suggesting these are pathogenic, with the p.Arg86Ter variant undetectable in our assays and the p.Met85Thr variant exhibiting reduced nuclear localisation. The pathogenic mechanisms underlying reduced activity of the novel elongated p.Tyr198Cysfs*18 variant is however unclear, although this variant also affected localisation. In contrast, two additional variants (p.Asp58Glu and p.Arg75Lys) had no discernible effects on nuclear localisation or transactivational activity despite in silico analysis predicting impaired DNA binding. Taken together, our data establish the likely pathogenicity of these SRY variants and improve diagnostic certainty for the patients in which they were identified. (AU) | |
| FAPESP's process: | 21/00684-3 - Next-generation sequencing and functional evaluation of genetic variants in individuals with DDS 46,XX testicular/ ovotesticular SRY-negative |
| Grantee: | Magnus Régios Dias da Silva |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 22/10804-9 - Multiple Endocrine Neoplasia type 2 (MEN 2) and Medullary Thyroid Carcinoma (TCM): new issues in developmental biology, genetics, immunology, epidemiology, mechanisms of disease and clinical management |
| Grantee: | Marina Malta Letro Kizys Polisel |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |