PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

Abstract

Context Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.

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

“…Klinefelter syndrome is characterized by the presence of a 47,XXY cell line and clinical features include tall stature, small testes, gynecomastia, primary gonadal failure, progressive germ cell loss, and infertility [20]. 46,XX/46,XY mosaicism and 46,XX/46,XY chimerism are associated with dysgenetic gonads, infertility, and a highly variable phenotype which may present with ambiguous genitalia at birth [21]. 46,XY DSD is usually characterized by ambiguous or female appearance of external genitalia with or without the presence of Mullerian structures as a result of under virilization in utero.…”

“…46,XX/46,XY mosaicism and 46,XX/46,XY chimerism are associated with dysgenetic gonads, infertility, and a highly variable phenotype which may present with ambiguous genitalia at birth [21]. 46,XY DSD is usually characterized by ambiguous or female appearance of external genitalia with or without the presence of Mullerian structures as a result of under virilization in utero. They can be further subdivided into three diagnostic categories: problems with gonadal development resulting in gonadal dysgenesis, biosynthetic defects causing impaired production of androgens (testosterone and dihydrotestosterone), or lack of androgen action due to end organ resistance to these hormones.…”

“…The 46,XY DSDs that result in impaired gonadal development are also associated with abnormalities of germ cell development predisposing to gonadal tumors and infertility, with the relative risk of malignancy dependent on the specific condition [22]. 46,XY complete gonadal dysgenesis (CGD), also known as Swyer syndrome, is characterized by failure of testicular development and formation of fibrous streak gonads which lack germ cells. Lack of production of AMH and testosterone results in a completely female appearance of the external genitalia and well developed Mullerian structures [23].…”

“…Impaired spermatogenesis is common in individuals with 5-α reductase deficiency [26]. 46,XY DSD can be caused by defects in androgen action, typically due to dysfunction of the androgen receptor (AR) [27]. DSD due to complete loss of function of the AR is termed Complete Androgen Insensitivity Syndrome (CAIS), whereas mutations that retain some residual function result in Partial Androgen Insensitivity Syndrome (PAIS).…”

“…Fertility is impaired in the majority of individuals with disorders of androgen action as a result of germ cell loss and/or failure of spermatogenesis [28]. 46,XX DSD is usually characterized by ambiguous or virilized genitalia as a result of fetal exposure to androgen excess and normal development of Mullerian structures and ovaries. Androgens may be derived from the fetal adrenal gland such as in CAH or placental aromatase deficiency, or rarely from exogenous sources such as transplacental passage of androgens from a maternal adrenal or ovarian tumor.…”