ESPEYB21 6. Differences of Sexual Development (DSD) and Gender Incongruence (GI) Clinical and Molecular Insights into SF1 Deficiency (3 abstracts)
6.6. A conserved NR5A1-responsive enhancer regulates SRY in testis-determination
Houzelstein D , Eozenou C , Lagos CF , Elzaiat M , Bignon-Topalovic J , Gonzalez I , Laville V , Schlick L , Wankanit S , Madon P , Kirtane J , Athalye A , Buonocore F , Bigou S , Conway GS , Bohl D , Achermann JC , Bashamboo A & McElreavey K
Nat Commun. 2024 Mar 30;15(1):2796. doi: 10.1038/s41467-024-47162-2. PMID: 38555298
Brief Summary: This study identified a conserved enhancer element located 5’ of the mammalian SRY gene through comparative genomic analysis, which plays a crucial role in the regulation of sexual differentiation. NR5A1 binds to this element. The researchers discovered two distinct hemizygous base pair substitutions within this NR5A1 binding site, both of which involve highly conserved residues: one in a sporadic case of XY sex reversal and the other in a large familial case of Y-linked 46,XY gonadal dysgenesis (1).
Despite the discovery of SRY over 30 years ago, the mechanisms that regulate its expression during testis determination remain poorly understood. In this study, the researchers first identified a conserved NR5A1-binding element in the open chromatin region upstream of the SRY gene. This 250bp long DNA region, designated E250, was accessible in vivo at the time of human testis determination, as shown by DNase-seq analysis of human fetal testis and single-cell ATAC-seq data from somatic cells in the human embryonic XY gonad. It was hypothesized that variants within this conserved region might influence human testis determination and development. To test this hypothesis, the team sequenced DNA from 358 individuals with unexplained 46,XY gonadal dysgenesis using Sanger sequencing or whole-genome sequencing. Two unique sequence variants were identified in the SRY 5’ flanking region, both located within the proposed E250 NR5A1-binding site.
In silico modeling predicted that single nucleotide substitutions disrupted the interaction between the NR5A1 protein and its corresponding response element. Further, a protocol differentiating human-induced pluripotent stem cells into gonadal progenitors (2) demonstrated that a deletion of the NR5A1 binding site in E250 was associated with a significant reduction of SRY expression during the critical phase of SRY induction.
The results of this comprehensive study underscore the importance of pathogenic variants in the regulatory elements of disease-causing genes in contributing to the etiology of 46,XY DSD. This study identified a novel cause for 46,XY DSD linked to SRY and proposed that the exquisite sensitivity to time- and dose-dependent thresholds might explain the phenotypic variability observed in familial cases.
References: 1. Kirtane, J. & Kaddu, S. 46XY disorder of sexual differentiation in five generations: a preliminary report. J. Prog. Paediatr. Urol. 17,75–79 (2014).2. Gonen N, Eozenou C, Mitter R, et al. In vitro cellular reprogramming to model gonad development and its disorders. Sci Adv. 2023;9(1):eabn9793. doi: 10.1126/sciadv.abn9793.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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