Characteristics of testicular dysgenesis syndrome and decreased expression of SRY and SOX9 in Frasier syndrome

Abstract

Frasier syndrome (FS) is characterized by chronic renal failure in early adulthood, varying degrees of gonadal dysgenesis, and a high risk for gonadal germ cell malignancies, particularly gonadoblastoma. Although it is known to arise from heterozygous splice mutations in intron 9 of the Wilms' tumor gene 1 (WT1), the mechanisms by which these mutations result in gonadal dysgenesis in humans remain obscure. Here we show that a decrease in WT1 + KTS isoforms due to disruption of alternative splicing of the WT1 gene in a FS patient is associated with diminished expression of the transcription factors SRY and SOX9 in Sertoli cells. These findings provide the first confirmation in humans of the results obtained by others in mice. Consequently, Sertoli cells fail to form the specialized environment within the seminiferous tubules that normally houses developing germ cells. Thus, germ cells are unable to fully mature and are blocked at the spermatogonial-spermatocyte stage. Concomitantly, subpopulations of the malignant counterpart of primordial germ cells/gonocytes, the intratubular germ cell neoplasia unclassified type (ITGCN), are identified. Furthermore, dysregulated Leydig cells produce insufficient levels of testosterone, resulting in hypospadias. Collectively, the impaired spermatogenesis, hypospadias and ITGCN comprise part of the developmental disorder known as 'testicular dysgenesis syndrome' (TDS), which arises during early fetal life. The data presented here show that critical levels of WT1 + KTS, SRY and SOX9 are required for normal Sertoli cell maturation, and subsequent normal spermatogenesis. To further study the function of human Sertoli cells in the future, we have established a human cell line.

Gonadal Tumor in Frasier Syndrome: A Review and Classification

“…Among the 46,XY Frasier syndrome cases, 32 (67%) had gonadal tumor, suggesting that the risk of gonadal tumor is higher than that reported in previous studies [60%; (ref. Eight cases of type 2 Frasier syndrome have been reported (8,12,(23)(24)(25)(26)(27)(28)(29). Although 5 of the cases initially visited clinics due to hypospadia or aplasia of testis (mean age at first visit: 1.0 AE 2.2 years), in most cases, these features did not lead to the diagnosis of Frasier syndrome.…”

“…Furthermore, sex reversal is observed in male mice deficient in the þKTS isoform of WT1 (7). In human patients with Frasier syndrome, a point mutation on IVS9 brings about downregulation of the þKTS isoform of WT1, which in turn diminishes SRY expression levels (8), and thereby impairs testicular development (7). Thus, male to female sex reversal will occur in pediatric Frasier syndrome patients with 46,XY (9).…”

Sertoli cell tumor and gonadoblastoma in an untreated 29-year-old 46,XY phenotypic male with Frasier syndrome carrying a WT1 IVS9+4C>T mutation

“…20,21 The phenotypic variability among different patients with the same mutation suggests that modifier genes and/or environmental factors may play a role in this variation. 17 In our patient, the constellation of the IVS9 + 4C>T mutation in the WT1 gene, the XY disorders of sexual differentiation, the onset of nephropathy in the second decade of life and the development of gonadoblastoma as well as Sertoli cell tumor support the diagnosis of Frasier syndrome. Our patient had predominantly undervirilized male external genitalia that led to a male sex of rearing.…”

“…16 In 46,XY patients, FS usually presents with complete gonadal dysgenesis, streak gonads and male to female sex reversal. 17 The external female phenotype leads to female sex of rearing. To our knowledge, 46,XY phenotypically male FS patients are very rare, 15,18,19 and amongst those genetically characterized only two have the same mutation as the patient in our report.…”

Gene Mutations Associated with Male Infertility

“…This gene is involved in testis development and differentiation (Zeng et al, 1998). The second target encoding a well described transcription factor SOX9, is probably regulated by mir-145 (Lian et al, 2009) and is required for testis determination and development but also for spermatogenesis (Schumacher et al, 2008). Finally, the third target gene encoding GAD45G, an apoptosis inducer and cell growth inhibitor in response to stress shock (Ying et al, 2005), is also a potential target of miR-383 (Lian et al, 2009).…”