Disease relevance of SRY

• True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological findings in a sporadic case [1].
• The origin of the patient's intersexuality is a postzygotic mutation of the SRY occurring in part of the gonadal tissue [1].
• The Wilms' tumor 1 (WT1) and sex-determining region of the Y chromosome (SRY) genes are essential for development of the mammalian gonads and mutations in these genes are associated with gonadal dysgenesis in humans [2].
• WT1 mutants associated with Denys-Drash syndrome (DDS), which is characterized by Wilms' tumor, pseudohermaphroditism, and nephropathy, fail to interact with SRY [2].
• In this study, we report a case of SRY-negative XX male with complete masculinization but infertility [3].

Psychiatry related information on SRY

• OBJECTIVE: To evaluate the safety and efficacy of once daily doses of tenofovir DF (TDF) administered in combination with other antiretroviral therapy (ART) in treatment-experienced HIV-1-infected patients with incomplete virological suppression [4].
• There were significant increases in heat pain threshold for TDF 25mug/h and TDB 35mug/h. Painful electrical stimulation failed to demonstrate an analgesic effect [5].

High impact information on SRY

• These differences begin to unfold during fetal development, when the Y-chromosomal Sry ("sex-determining region Y") gene is activated in males and acts as a switch that diverts the fate of the undifferentiated gonadal primordia, the genital ridges, towards testis development [6].
• Mammalian sex determination is governed by the presence of the sex determining region Y gene (SRY) on the Y chromosome [7].
• Mutations in the human SRY-related gene, SOX9, located on chromosome 17, have recently been associated with the sex reversal and skeletal dysmorphology syndrome, campomelic dysplasia [8].
• These data indicate that, in addition to a role in testis determination, SRY may have other functions [corrected] [9].
• We show the marsupial SRY gene cannot be exclusively coupled to Sertoli cell differentiation, as this gene is expressed in the male fetus from several days before genital ridge formation until 40 days after birth [9].

Chemical compound and disease context of SRY

• In this report we describe the clinical, endocrinological and molecular data of a patient with complete 46,XY gonadal dysgenesis caused by a de novo mutation affecting SRY amino acid phenylalanine at position 67 (F67L), located within the highly conserved high mobility group (HMG) box coding region of the gene [10].
• TDF is selectively inactivated during protein synthesis inhibition by cycloheximide and at a late stage of adenovirus infection, thus accounting for the loss of RNA Pol III-mediated transcription of the tRNA and VA RNA genes under these conditions [11].
• BACKGROUND: Tenofovir (TDF) is an adenosine nucleotide analogue that has been approved for the treatment of HIV-1 infection [12].
• Presence of M184V mutation was related with a greater reduction in HIV RNA during d4T/TDF exposure [13].
• The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned [14].

Biological context of SRY

• In the SRY PCR product of gonadal DNA, the wild-type and two point mutations were present in the patient's sequence, simulating a heterozygous state of a Y-chromosomal gene: one of the mutations was silent, while the other encoded for a nonconservative amino acid substitution from leucine to histidine [1].
• Using a Y chromosome polymerase chain reaction (PCR) walking strategy and inverse PCR, we found that the abnormal recombination occurred between retroviral long terminal repeats located at Xp22.33 (position 0.95 Mb; inside the pseudoautosomal regions) and Yp11.2 (4.20 Mb) downstream of the sex-determining region Y (SRY) gene [15].
• SRY and SOX9, members of the family of high-mobility group (HMG) domain transcription factors, are both essential for testis formation during human embryonic development [16].
• Coexpression of AR and SRY caused marked repression of AR transcriptional activity on a series of androgen-responsive reporter genes [17].
• Using normal or mutant SRY-beta-galactosidase and SOX9-beta-galactosidase fusion proteins in transfection studies involving COS-7 cells, we have identified two nuclear localization signals (NLSs) within the HMG domains of both proteins that can independently direct the fusion proteins into the nucleus [16].

Anatomical context of SRY

• Functional studies of SRY in a cell line from embryonic gonadal ridge demonstrated activation of a gene-regulatory pathway leading to expression of MIS [18].
• Analysis of lymphocyte DNA from the respective fathers revealed that they carry both the wild-type and the mutant version of the SRY gene [19].
• The SRY gene of five subjects with 46,XY complete gonadal dysgenesis (46,XY karyotype, completely female external genitalia, normal Müllerian ducts, and streak gonads) was evaluated for possible mutations in the coding region by using both single-strand conformation polymorphism (SSCP) assay and DNA sequencing [20].
• In order to identify genetic defects associated with subjects with the disease, we performed molecular analyses of the SRY gene in DNA from blood leukocytes and gonadal tissue in 12 true hermaphrodites with different karyotypes [21].
• By immunohistochemistry SRY protein was detected in all ovotestes, predominantly in Sertoli and germ cells [22].

Associations of SRY with chemical compounds

• Finally, these data demonstrated that NPCs exposed to cocaine underwent differentiation into cells expressing neuronal markers that was associated with an inhibition of SOX2 (SRY-related HMG-box gene 2), a transcription factor that inhibits NPC differentiation [23].
• In this study, we demonstrate that interaction of the human SRY with histone acetyltransferase p300 induces the acetylation of SRY both in vitro and in vivo at a single conserved lysine residue [24].
• In calmidazolium-treated cells, the dramatic reduction in nuclear entry of SRY and an SRY-c-NLS mutant was not observed for two SRY-n-NLS mutants [25].
• An A-to-G transition was detected which leads to an exchange of a tyrosine by a cysteine in the SRY protein [26].
• This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD [27].

Physical interactions of SRY

• The implications of the present results are discussed regarding (a) the apparent dual function of certain basic amino acid residues in the HMG domain of SRY in both DNA binding and in nuclear localization and (b) the possible control of SOX9 in early gonadal differentiation at the level of nuclear translocation [16].
• Here we report that WT1 binds to and acts synergistically with SRY to activate transcription from a promoter containing SRY-binding sites [2].
• The proximity of SRY to the pseudoautosomal region (PAR) is highly conserved and thus most effectively stabilizes the pseudoautosomal boundary on the Y (PABY) in simians [28].
• We hypothesize that SIP-1 could connect SRY to other transcription factors providing SRY for its missing trans-regulation domain [29].
• Recombinant SRY protein was able to bind to the same core sequence AACAAAG recognized by TCF-1 in a sequence dependent manner [30].

Regulatory relationships of SRY

• SRY interacts with and negatively regulates androgen receptor transcriptional activity [17].
• SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors [31].
• It is suggested here that, rather than acting as a transcriptional activator, the SRY gene acts to inhibit its paralogue SOX3, which in turn inhibits an ancient autosomal sex-determining gene SOX9 [32].
• The WT1 transcription factor regulates SRY expression during the initial steps of the sex determination process in humans, activating a gene cascade leading to testis differentiation [33].
• DNA from the blood of 120 men and women and from 38 single lymphocytes was amplified by polymerase chain reaction (PCR) with the SRY and control (ZP3) gene primers [34].

Other interactions of SRY

• Here we show that SRY and the Sox protein SOX6 colocalize with splicing factors in the nucleus and are dynamically redistributed following the blockage of splicing in living cells [35].
• SRY protein expression was increased by proteosome inhibitors and by the androgen-liganded AR in transient and stable transfectants [17].
• This interaction is mediated by the WT1 zinc-finger domain and the SRY HMG box [2].
• In amniotes, the banded krait minor (Bkm) minisatellite (GATA), the human telometric sequence (TTAGGG)7, and the Y-specific genes, ZFY and SRY, are associated with a particular sex [36].
• The protein levels of DAX-1, SRY and WT-1 were significantly higher in the bald scalp (p = 0.003, 0.004 and 0.03, respectively) [37].

Analytical, diagnostic and therapeutic context of SRY

• Recently, studies using reverse transcriptase polymerase chain reaction (RT-PCR) have detected paternal transcripts for the Y-linked genes, ZFY and SRY, and the myotonic dystrophy associated protein kinase gene, DK, as early as the late pronucleate one-cell stage [38].
• The significance of the C-terminal basic cluster (SRY residues 130-134) is uncertain, however, as its activity in cell culture varies with assay conditions [39].
• The SRY mutation in the XY female reported here occurred de novo, as sequence analysis showed that it was not present in her father or other family members [40].
• Using Southern blotting, polymerase chain reaction, denaturing gradient gel electrophoresis and direct sequencing, we analyzed deletions and point mutations in the SRY gene [41].
• Indirect immunofluorescence and confocal microscopy show that the mouse SRY colocalizes with KRAB-O in nuclear dots in transiently transfected COS7 cells and primary fetal mouse gonadal cells [42].

References