Mutations in the SRY, DAX1, SF1 and WNT4 genes in Brazilian sex-reversed patients

Abstract

In most mammals, male development is triggered by the transient expression of the SRY gene, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad. Mutation studies have identified several genes essential for early gonadal development. We report here a molecular study of the SRY, DAX1, SF1 and WNT4 genes, mainly involved in sexual determination, in Brazilian 46,XX and 46,XY sex-reversed patients. The group of 46,XX sex-reversed patients consisted of thirteen 46,XX true hermaphrodites and four 46,XX males, and was examined for the presence of the SRY gene and for the loss of function (inactivating mutations and deletions) of DAX1 and WNT4 genes. In the second group consisting of thirty-three 46,XY sex-reversed patients we investigated the presence of inactivating mutations in the SRY and SF1 genes as well as the overexpression (duplication) of the DAX1 and WNT4 genes. The SRY gene was present in two 46,XX male patients and in none of the true hermaphrodites. Only one mutation, located outside homeobox domain of the 5' region of the HMG box of SRY (S18N), was identified in a patient with 46,XY sex reversal. A novel 8-bp microdeletion of the SF1 gene was identified in a 46,XY sexreversed patient without adrenal insufficiency. The dosage of DAX1 and WNT4 was normal in the sex-reversed patients studied. We conclude that these genes are rarely involved in the etiology of male gonadal development in sex-reversed patients, a fact suggesting the presence of other genes in the sex determination cascade.

Gonadal Development and Tumor Formation at the Crossroads of Male and Female Sex Determination

“…Our knowledge on normal human gonadal development and sexual differentiation is only fragmentary and results mainly from casuistically described human phenotypes following from specific genetic alterations, interpreted in the light of the above mentioned animal and in vitro studies [Biason-Lauber et al, 2004;Canto et al, 2004;Domenice et al, 2004;Parma et al, 2006;Barbaro et al, 2008;Tomaselli et al, 2008;Biason-Lauber and Schoenle, 2009;Hersmus et al, 2009;Lourenco et al, 2009;Meduri et al, 2010;Tannour-Louet et al, 2010]. However, gene expression studies on human fetal gonadal material are now emerging and confirm to a certain extent previously suggested parallelisms between the mouse and human process of gonadal development [Duffin et al, 2009;Houmard et al, 2009].…”

WNT4 and Sex Development

“…Searches for clinically relevant WNT4 mutations sometimes in large cohorts of such patients were unsuccessful [Domenice et al, 2004]. We described a woman with absent Müllerian structures (uterine and fallopian tubes) who had unilateral renal agenesis ( fig.…”

NHERF2/SIP-1 Interacts with Mouse SRY via a Different Mechanism than Human SRY

“…Most of the sex-reversing mutations described in the human SRY open reading frame are located in the HMG domain. However, several mutations have been described that affect either the N-terminal domain (10,11) or the C-terminal domain, where the two mutations described affect the last 50 amino acids either by a stop codon (12) or by a frameshift mutation (13). These mutations lead to the deletion of the protein region that interacts with SIP-1 (also called NHERF2 or E3KARP), a PDZ domain containing protein that we previously isolated and characterized for its interaction with the human SRY protein (14).…”