Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

Hattori, Atsushi; Fukami, Maki

doi:10.3390/biom13040691

Cited by 6 publications

(10 citation statements)

References 132 publications

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“…COUP-TFs are members of the steroid/thyroid hormone receptor superfamily. COUP-TF homologs, which have been cloned from humans, suggest that their protein sequences are highly homologous across species, defining functional conservation ( 62 , 78 ). NR2F2 is primarily expressed in mesenchymal cells ( 78 ).…”

Section: Molecular Etiologies Of 46xx T-dsd and Ot-dsdmentioning

confidence: 99%

“…In developing testicular tissue, NR2F2 expression is observed in Leydig cells from 7 to 10 gw but is downregulated at 15 gw and repressed throughout fetal life. Previous studies concluded that NR2F2 repression is important for fetal Leydig cell differentiation ( 62 ). According to rodent studies, the target genes of NR2F2 in Leydig cells are AMHR2 , INSL3 , and genes encoding steroidogenic enzymes ( 62 ).…”

Section: Molecular Etiologies Of 46xx T-dsd and Ot-dsdmentioning

confidence: 99%

“…Previous studies concluded that NR2F2 repression is important for fetal Leydig cell differentiation ( 62 ). According to rodent studies, the target genes of NR2F2 in Leydig cells are AMHR2 , INSL3 , and genes encoding steroidogenic enzymes ( 62 ).…”

Section: Molecular Etiologies Of 46xx T-dsd and Ot-dsdmentioning

confidence: 99%

“…All four patients were 46,XX with testicular development. The mechanism underlying testicular development associated with NR2F2 variants is not clear ( 62 ). Bashamboo et al.…”

Section: Molecular Etiologies Of 46xx T-dsd and Ot-dsdmentioning

confidence: 99%

“…All genetic etiologies causing 46,XX T-DSD can also lead to 46,XX OT-DSD ( 50 , 53 ). SRY translocations, CNVs of FGF9 , NR0B1 , NR2F2 , SOX3 , SOX9 , SOX10 , and SPRY2 , and sequence variants of NR5A1 , NR2F2 , RSPO1 , SOX9 , WNT4 , WNT2B , and WT1 are responsible for the genetic mechanisms associated with 46,XX T/OT-DSD ( 62 ).…”

Section: Introductionmentioning

confidence: 99%

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Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

Yavas Abalı,

Guran

2024

Front. Endocrinol.

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Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.

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Section: Molecular Etiologies Of 46xx T-dsd and Ot-dsdmentioning

confidence: 99%

Section: Molecular Etiologies Of 46xx T-dsd and Ot-dsdmentioning

confidence: 99%

Section: Molecular Etiologies Of 46xx T-dsd and Ot-dsdmentioning

confidence: 99%

“…All four patients were 46,XX with testicular development. The mechanism underlying testicular development associated with NR2F2 variants is not clear ( 62 ). Bashamboo et al.…”

Section: Molecular Etiologies Of 46xx T-dsd and Ot-dsdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

Yavas Abalı,

Guran

2024

Front. Endocrinol.

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COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors

Ferreira

Kizys

Gama

et al. 2023

Preprint

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The absence of expression of the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) of bipotential gonads leads to ovarian development. However, genetic variants in NR2F2/COUP-TFII represent a novel cause of SRY-negative 46,XX testicular/ovotesticular differences of sex development (T/OT-DSD). Thus, we hypothesized that COUP-TFII is part of the ovarian developmental network. We examined NR2F2/COUP-TFII expression and the genetic network under its regulation in human gonadal cells by analyzing single cell RNA-sequencing datasets of fetal gonads, differentiating induced pluripotent stem cells into bipotential gonad-like cells in vitro, and generating a NR2F2 knockout (KO) in the human granulosa-like cell line COV434. NR2F2 expression is highly upregulated during the bipotential gonad development, being detected in ESGCs. We identified that NR2F2 ablation in COV434 cells downregulated markers of ESGC and pre-granulosa cells, suggesting that COUP-TFII has a role in maintaining a multipotent state necessary for commitment to the ovarian development. We propose that impairment of COUP-TFII function may disrupt the transcriptional plasticity of ESGCs and instead drive them into commitment to the testicular pathway.

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COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors

Ferreira,

Kizys,

Gama

et al. 2024

Cell Biosci

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Background The absence of expression of the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) leads bipotential gonads into ovarian development. However, genetic variants in NR2F2, encoding three isoforms of the transcription factor COUP-TFII, represent a novel cause of SRY-negative 46,XX testicular/ovotesticular differences of sex development (T/OT-DSD). Thus, we hypothesized that COUP-TFII is part of the ovarian developmental network. COUP-TFII is known to be expressed in interstitial/mesenchymal cells giving rise to steroidogenic cells in fetal gonads, however its expression and function in ESGCs have yet to be explored. Results By differentiating induced pluripotent stem cells into bipotential gonad-like cells in vitro and by analyzing single cell RNA-sequencing datasets of human fetal gonads, we identified that NR2F2 expression is highly upregulated during bipotential gonad development along with markers of bipotential state. NR2F2 expression was detected in early cell populations that precede the steroidogenic cell emergence and that retain a multipotent state in the undifferentiated gonad. The ESGCs differentiating into fetal Sertoli cells lost NR2F2 expression, whereas pre-granulosa cells remained NR2F2-positive. When examining the NR2F2 transcript variants individually, we demonstrated that the canonical isoform A, disrupted by frameshift variants previously reported in 46,XX T/OT-DSD patients, is nearly 1000-fold more highly expressed than other isoforms in bipotential gonad-like cells. To investigate the genetic network under COUP-TFII regulation in human gonadal cell context, we generated a NR2F2 knockout (KO) in the human granulosa-like cell line COV434 and studied NR2F2-KO COV434 cell transcriptome. NR2F2 ablation downregulated markers of ESGC and pre-granulosa cells. NR2F2-KO COV434 cells lost the enrichment for female-supporting gonadal progenitor and acquired gene signatures more similar to gonadal interstitial cells. Conclusions Our findings suggest that COUP-TFII has a role in maintaining a multipotent state necessary for commitment to the ovarian development. We propose that COUP-TFII regulates cell fate during gonad development and impairment of its function may disrupt the transcriptional plasticity of ESGCs. During early gonad development, disruption of ESGC plasticity may drive them into commitment to the testicular pathway, as observed in 46,XX OT-DSD patients with NR2F2 haploinsufficiency.

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Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

Cited by 6 publications

References 132 publications

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development

COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors

COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors

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