The Natural History of a Man With Ovotesticular 46,XX DSD Caused by a Novel 3-Mb 15q26.2 Deletion Containing NR2F2 Gene

Abstract

Gonadal sex determination is a complex genetic process by which an embryonic primordium is driven to form an ovary or a testis, which requires a delicate dosage balance involving many genes. Disruption in this molecular pathway can lead to differences of sex development (DSD). Although some genetic mechanisms leading to 46,XY DSD have been elucidated, little is known about copy-number variation (CNV) causing testicular or ovotesticular 46,XX DSD. We describe a 20-year natural history of a man with SRY-negative 46,XX who was born with atypical male external genitalia, aortic coarctation, and bilateral blepharophimosis-ptosis. The molecular study identified a de novo heterozygous 3-Mb 15q26.2 deletion, a gene-poor locus containing NR2F2, which encodes the nuclear receptor COUP-TFII that is highly expressed in ovary and cardiac arteries. Immunohistochemistry confirmed the low COUP-TFII expression on his ovotestis tissue. Monosomy of 15q26.2, encompassing the NR2F2 gene, may act as a Z-factor regulating the male sex determination negatively. This finding supports a novel type of CNV resulting in DSD in an individual who developed male puberty spontaneously.

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

“…The orphan nuclear receptor NR2F2 gene, which encodes the transcription factor chicken ovalbumin upstream promoter transcription factor 2 (COUP-TF2), has been described as a "pro-ovary and anti-testis" gene following the identification of two frameshift variants in three syndromic 46,XX children, one with ovarian dysgenesis and the other with OT DSD, associated with congenital heart disease and variable somatic anomalies including blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) [81]. A 3 Mb deletion containing the NR2F2 gene was also described in an individual with 46,XX OT DSD with a similar phenotype [82]. BPES in usually caused by heterozygous loss-of-function FOXL2 variants with or without ovarian dysgenesis.…”

“…COUP-TF2 is expressed at the same time as WT1 in early gonadal embryogenesis [83] and it regulates negatively the expression of the pro-testis Sox9 gene in the osteogenic mesenchyme. Hence, it is hypothesized that testis development in these individuals with NR2F2 mutations is driven by SOX9 activation via WT1 [82].…”

Male Hypogonadism and Disorders of Sex Development

“…Insufficient expression of pro-ovarian genes has been proposed as the underlying pathogenesis in patients with loss-of-function mutations or deletions of RSPO1 (97-100) or WNT4 (101). More recently, 46,XX testicular or ovotesticular DSD has been attributed to mutations in NR5A1, encoding SF1 (102-107), WT1 (108) and NR2F2, encoding COUP-TF2 (109,110).…”

COUP-TFII in Health and Disease

“…Interestingly, COUP-TFII deletion in adult mice has no effect on testosterone levels and Leydig cells appear normal in number, suggesting that the receptor is dispensable for Leydig function in adults [132]. Recently, a 3 Mb deletion of the locus containing NR2F2 was described in an SRY 46, XX male with spontaneous male puberty, further implicating COUP-TFII in sex determination [138].…”

“…The association of COUP-TFII to cancer progression has been widely investigated and it has received more attention since the demonstration that the NR is a major player in cell differentiation and cell metabolism. Expression of COUP-TFII and other nuclear receptors (e.g., LXRβ, RARα, REVERBα) is relatively high in cancer cells tested by high-throughput qPCR; moreover, the receptor forms a cluster with RXRα, HNF4 (α and β) and PPARγ, reflecting known functional associations and is relatively near to ERα, who is implicated in breast cancer progression (see below for details) [138]. Interestingly, COUP-TFII negatively correlates with the resistance to some chemotherapy agents, especially to derivatives of microtubule-targeting drugs (e.g., Taxol or colchicine), pointing to a putative association with a cytoskeleton organization and EMT [156].…”