Familial Frameshift SRY Mutation Inherited from a Mosaic Father with Testicular Dysgenesis Syndrome

Abstract

This observation of somatic and germinal mosaicism for a SRY mutation may explain the variable penetrance in some familial gonadal dysgenesis. Importantly, the present report is the first one describing the association of SRY mutation in a male with TDS. This suggests that mutations in a sex-determining gene may contribute to the pathogenesis of TDS.

A Brief Review of the Link between Environment and Male Reproductive Health: Lessons from Studies of Testicular Germ Cell Cancer

“…This hypothesis seemed to be in line with the reports of synchronous trends in TGCC, sperm counts, cryptorchidism and hypospadias [37]. We [30] and others [29,38] have since been testing the hypothesis and found further evidence of a role of rare mutations in genes that control androgen action and Sertoli cell function in DSD patients with signs and symptoms of TDS. However, most patients with TGCC have much less obvious manifestations of DSD, which, in addition to the tumour, include an increased risk of cryptorchidism and impaired spermatogenesis [19,39].…”

“…Although a possible link between hypospadias and TGCC has been questioned [25], more recent studies have shown a clear association, which is however weaker than that between TGCC and cryptorchidism [26,27]. In addition, an association between TGCC and severe forms of hypospadias, as seen in patients with disorders of sex development (DSD), has been known since the early studies of Scully [28] and recently confirmed in patients with heterogeneous genetic phenotypes, such as mutations in SRY [29] or androgen receptor gene [17,30]. However, in the vast majority of patients with TGCC, no mutations have been found.…”

Identification of a Novel Androgen Receptor Mutation in a Family With Multiple Components Compatible With the Testicular Dysgenesis Syndrome

“…The p.Ile738Met mutation described here is a rare example of a clear genetic component in the pathogenesis of TDS. Recently, a novel SRY frame-shift mutation found in a mosaic state in a patient with testicular cancer, cryptorchidism, hypospadias, and oligoasthenozoospermia was described (19). Thus, the full TDS phenotype including TGCT has now been observed in individuals with mutations affecting 2 different genes involved in virilization and testicular development.…”

Copy Number Variations of the Azoospermia Factor Region and SRY Are Not Associated with the Risk of Hypospadias

“…However, considering the limited sensitivity of STS-PCR assays and the small number of individuals examined, further studies are required to clarify the association between AZF-linked CNVs and hypospadias. In addition, although mosaic loss-of-function mutations of SRY have been associated with both SF and hypospadias [Isidor et al, 2009;Shahid et al, 2010], CNVs of the SRY locus have rarely been analyzed in hypospadias patients. Here, we performed MLPA analysis to evaluate the frequency of CNVs of the AZF region and SRY in 89 Japanese children with hypospadias.…”