Alternative titles; symbols
HGNC Approved Gene Symbol: SRY
SNOMEDCT: 763683004;
Cytogenetic location: Yp11.2 Genomic coordinates (GRCh38): Y:2,786,855-2,787,682 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Yp11.2 | 46XX sex reversal 1 | 400045 | X-linked dominant | 4 |
| 46XY sex reversal 1 | 400044 | Y-linked | 3 |
SRY encodes a transcription factor that is a member of the high mobility group (HMG)-box family of DNA binding proteins.
Sinclair et al. (1990) identified a gene, which they named SRY (sex-determining region Y), within a 35-kb sex-determining region on the human Y chromosome that was adjacent to the pseudoautosomal boundary. The mouse homolog Sry was subsequently cloned and found to be present in Sxr-prime mice, which have the smallest part of the Y chromosome known to be sex-determining (Gubbay et al., 1990). Furthermore, Sry was deleted from a mutant Y chromosome that was no longer sex-determining (Gubbay et al., 1990).
Su and Lau (1993) found that the SRY open reading frame encodes a deduced 204-amino acid protein with a calculated molecular mass of 24 kD. There is a DNA-binding HMG motif in the middle of the protein.
Capel et al. (1993) found that a circular Sry transcript consisting of a single exon represented more than 90% of Sry transcripts in adult mouse testis. In contrast, developing mouse genital ridge exclusively expressed linear Sry transcripts. Circular Sry transcripts were not detected in any other mouse tissue examined and were most likely noncoding. Capel et al. (1993) noted that the human SRY gene is transcribed into a linear form only and lacks the flanking inverted repeats required for circular splicing.
Goodfellow and Lovell-Badge (1993) provided a major review of SRY and sex determination in mammals.
From the study of normal males and females, persons with abnormal numbers of sex chromosomes, and persons carrying variant Y chromosomes, a factor (or factors) that determines the differentiation of the indifferent gonads into testes is known to be located on the Y chromosome and specifically on the short arm; this was designated testis-determining factor (TDF) in the 1960s. (See Mendelian Inheritance in Man, 4th ed., figure 1, page lix, 1975.)
Mittwoch (1992) argued that the 'dogma' that all differences distinguishing male and female mammals can be traced to the presence or absence of a single gene encoding a testis-determining factor lacks, as she said, 'biological validity.' She suggested that the genotype of the functional, i.e., fertile, male differs from that of a functional female by the presence of multiple Y-chromosomal genes in association with but a single X chromosome.
Lahr et al. (1995) used RT-PCR to investigate the transcription of the Sry gene in mice. The gene was transcribed in the hypothalamus, midbrain, and testis of adult male but not adult female mice. Whereas the transcripts in the adult testis were circular, those in brain were linear and therefore capable of translation. Lahr et al. (1995) hypothesized that some male specific properties of the brain may be generated directly by the SRY gene product.
With use of reporter plasmids, gel shift assays, and transfection experiments, Hossain and Saunders (2001) determined that the product of the WT1 gene (607102) transactivates SRY by binding to its promoter region. They also found that WT1 carrying any of 4 common mutations causing Denys-Drash syndrome failed to activate the SRY promoter.
Li et al. (2001) found that the R133W SRY mutation (607102.0019), which lies within the HMG DNA-binding domain, had little or no effect on specific DNA binding and bending assays, but resulted in a significant change in cellular location of SRY upon transfection into COS-7 cells and into a male rat gonadal ridge embryogenic cell line. In both model cell systems, wildtype SRY localized to the nuclear compartment, whereas the mutant SRY showed a broad distribution in the cytoplasm and nucleus similar to that observed with deletion of the C-terminal nuclear localization signal (NLS).
Sekido and Lovell-Badge (2008) demonstrated that Sry binds to multiple elements within a Sox9 (608160) gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with steroidogenic factor-1 (SF1) an orphan nuclear receptor encoded by the gene Nr5a1 (184757). Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Sekido and Lovell-Badge (2008) concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and the failure of these mechanisms in cases of sex reversal.
By yeast 2-hybrid screening of a human testis cDNA library, Sato et al. (2011) identified RPS7 (603658) and RPL13A (619225) as SRY-interacting proteins. Pull-down assay confirmed that the HMG box of SRY was required for its interaction with RPS7 and RPL13A. In transiently transfected COS1 cells, SRY, RPS7, and RPL13A colocalized in nuclear speckles.
Hansen et al. (2013) found that the mouse Sry circular RNA contains 16 putative microRNA-138 (MIR138; see 613394)-binding sites. They showed that Sry bound Mir138 and functioned as an Mir138 sponge, reducing the ability of Mir138 to downregulate expression of a reporter gene.
Kuroki et al. (2013) found that Jmjd1a (611512) regulates expression of the mammalian Y chromosome Sry. Jmjd1a directly and positively controls Sry expression by regulating H3K9me2 marks. Kuroki et al. (2013) found that Jmjd1a-null mice that were XY were frequently sex reversed, either partially, with a testis and an ovary (12 of 58 animals), or completely, with 2 ovaries (34 of 58 animals). In contrast, all Jmjd1a wildtype and heterozygous XY mice had 2 testes. Kuroki et al. (2013) concluded that their studies revealed a pivotal role of histone demethylation in mammalian sex determination.
Su and Lau (1993) determined that SRY is an intronless gene that spans 3.8 kb. Analysis of the proximal flanking region revealed 2 GC-rich regions containing several Sp1 (189906)-binding sites. The gene also contains a TATAAA motif for the binding of TFIID (TAF5; 601787) and a kappa B enhancer element for the binding of NF-kappa-B (see 164011).
TDF was ultimately mapped to the human Y chromosome by molecular examination of sex-reversed patients. Analysis of 4 XX males with testes who had minute portions of the Y material translocated to the X chromosome was critical in defining the sex-determining region on the human Y chromosome (Palmer et al., 1989; Sinclair et al., 1990). The sex-determining region on the human Y chromosome was later defined to a 35-kb region of Y-specific DNA adjacent to the pseudoautosomal boundary (Sinclair et al., 1990).
Behlke et al. (1993) found that 2 RNAs hybridized to a 4,741-bp genomic segment of the sex-determining region of the human Y chromosome: one transcript deriving from SRY, and a second transcript cross-hybridizing to a pseudogene located 2.5 kb 5-prime of the SRY open reading frame. Analysis of the SRY transcript suggested that the entire SRY protein is encoded by a single exon.
46,XY Complete Gonadal Dysgenesis
Jager et al. (1990) analyzed the SRY gene in 12 XY sex-reversed females (400044) and identified a de novo 4-bp deletion (480000.0001) in a conserved DNA-binding motif in 1 patient.
Hawkins et al. (1992) studied the SRY gene in 5 phenotypic females with complete gonadal dysgenesis and a 46,XY karyotype reported by Berkovitz et al. (1991). They used single-strand conformation polymorphism assay and DNA sequencing to screen the open reading frame and identified mutations in 3 of the 5 patients. Like all the previously described SRY mutations, these mutations--2 point mutations (480000.0006 and 480000.0007) and a single-base deletion (480000.0008)--altered the putative DNA-binding region of the SRY protein.
Hawkins (1993) performed a mutation analysis of the SRY gene in XY females. He noted that 11 mutations had been described at that time, and all were within the DNA-binding HMG-box region of the protein.
Cameron and Sinclair (1997) stated that 26 different mutations in the SRY gene have been found in individuals with a 46,XY karyotype. They cited reports stating that no polymorphisms had been described in SRY among 50 normal males. De novo mutations in the SRY HMG-box region almost always resulted in 46,XY unambiguous females with no testicular differentiation. They found 5 reports of familial 46,XY complete gonadal dysgenesis associated with mutations in the SRY HMG-box region. In 4 of these reports, the father carried the same SRY mutation as his 46,XY daughter. None of the mutations appeared to be polymorphisms. Explanations for the sex reversal associated with these familial SRY mutations included paternal gonadal mosaicism for the mutation (yet to be proven) and incomplete penetrance of the mutation. Support for a penetrance effect came from murine studies in which at least 3 autosomal recessive alleles were found to interact with Y-chromosome alleles, resulting in the genesis of XY ovaries and true hermaphrodites (Eicher and Washburn, 1986). Cameron and Sinclair (1997) noted that timing and expression of SRY are exquisitely regulated and probably must reach a threshold. Consequently, a given mutation in SRY against a particular genetic background might produce sufficient SRY expression to reach the threshold required; testis formation can then ensue, accounting for an unaffected father.
Uehara et al. (2002) found missense mutations in the SRY gene in 2 of 3 patients with the complete form of XY gonadal dysgenesis. Combined with the results of a previous study (Uehara et al., 1999) in which 2 of 3 complete-type patients showed SRY abnormalities, the incidence was estimated at 67%, which is higher than previously thought. A metaanalysis of patients with SRY abnormalities showed an incidence of 52.5% for gonadal tumor formation in patients with SRY abnormalities. Uehara et al. (2002) gave a useful tabulation of the SRY abnormalities that had been described.
Harley et al. (2003) examined the SRY gene from 4 XY females, each with a missense mutation of a conserved arginine in either 1 of the 2 NLSs of the SRY HMG box. In all cases, mutant SRY protein was partly localized to the cytoplasm, whereas wildtype SRY was strictly nuclear. Each NLS can independently direct nuclear transport of a carrier protein in vitro and in vivo, with mutations in either affecting the rate and extent of nuclear accumulation. The N-terminal NLS function is independent of the conventional NLS-binding importins and requires cytoplasmic transport factors, whereas the C-terminal NLS is recognized by importin-beta (KPNB1; 602738). The SRY mutant R133W (480000.0019) showed reduced importin-beta binding as a direct consequence of the sex-reversing C-terminal NLS mutation. Of the 3 other N-terminal NLS mutants examined, 1 unexpectedly showed a marked reduction in importin-beta binding, whereas the other 2 showed normal importin-beta binding, suggesting defects in the importin-independent pathway. Harley et al. (2003) concluded that SRY normally requires the 2 distinct NLS-dependent nuclear import pathways to reach sufficient levels in the nucleus for sex determination. The study documented cases of human disease that were explained, at a molecular level, by the impaired ability of a protein to accumulate in the nucleus.
46,XY True Hermaphroditism
Braun et al. (1993) reported a 46,XY true hermaphrodite who had a mutation of SRY in gonadal DNA but not in leukocyte DNA, suggesting that the mutation was postzygotic. Because of this finding, Fuqua et al. (1997) attempted to determine whether postzygotic mutations of SRY might explain the numerous cases of gonadal dysgenesis in which no SRY mutation was detected in leukocyte DNA. They evaluated 16 subjects with 46,XY gonadal dysgenesis who had a normal SRY sequence in leukocyte DNA, 5 of them having 46,XY complete gonadal dysgenesis. They did not find mutations in gonadal DNA from any of 16 subjects and concluded that postzygotic mutations of SRY are a rare cause of 46,XY gonadal dysgenesis.
Maier et al. (2003) reported a 46,XY true hermaphrodite who had a mutation in the SRY gene (480000.0006). The father, his 3 brothers, and his first-born son carried the identical mutation without phenotypic effects. Maier et al. (2003) concluded that the mutated protein retained enough activity to allow normal development in some individuals.
46,XX Gonadal Dysgenesis, Complete or Partial
Margarit et al. (2000) studied a 46,XX true hermaphrodite and found that Yp-specific sequences, including the SRY gene, had been transferred to the long arm of one of the X chromosomes at the Xq28 level. The derivative X chromosome of the patient lacked q-telomeric sequences. The authors suggested that this was the first report of a Yp/Xq translocation. The coexistence of testicular and ovarian tissue in the patient may have arisen by differential inactivation of the Y-bearing X chromosome, in which Xq telomeric sequences were missing.
Sharp et al. (2005) studied causes of incomplete masculinization in 15 individuals with segments of Yp translocated onto Xp. Expression studies showed little evidence for the spreading of X inactivation into Yp chromatin; however, in several cases, disruption of gene expression occurred independently of X inactivation, suggesting position effects resulting from chromosomal rearrangement. In particular, 5 of 6 translocation carriers with an intersex phenotype had either translocation breakpoints very close to SRY, or disrupted expression of genes near SRY in a manner unrelated to X inactivation. Southern blot analysis suggested the presence of a cryptic rearrangement 3 to 8 kb proximal to SRY in 1 case. Sharp et al. (2005) suggested that incomplete masculinization in cases of X/Y translocation is a result of disruption of normal SRY expression by position effects rather than X inactivation.
Zenteno et al. (1997) described a Mexican family in which 2 brothers, aged 28 and 26, were thought to be instances of 'classic' XX males without genital ambiguity but were found to be negative for several Y-chromosome sequences, including SRY. The data suggested that an inherited loss-of-function mutation in a gene participating in the sex-determining cascade can induce normal male sexual differentiation in the absence of SRY.
Mosaicism
Shahid et al. (2005) performed molecular genetics studies in 3 Turner syndrome patients all presenting with 45,X/46,XY mosaic karyotype. Two patients carried mutations within the HMG box, and 1 patient carried a frameshift mutation downstream of the HMG box. The authors suggested that lack of a second sex chromosome in a majority of cells (mosaic karyotype and mutation in the SRY gene) in these patients may have triggered the short stature.
Lange et al. (2009) identified 60 unrelated individuals with isodicentric (idic) or isocentromeric (iso) Y chromosomes, 51 of which apparently arose via a palindromic mechanism, yielding an idicYp in 49 cases and an idicYq in 2 cases, whereas the remaining 9 arose via recombination in heterochromatic sequences, yielding an idicYp in 2 cases and an isoYp in 7 cases. As expected, the 2 individuals carrying the idicYq chromosomes lacked the SRY gene and were phenotypic females; however, 18 of the 58 idicYp and isoYp individuals, who had 2 copies of SRY, were also 'sex-reversed' and raised as females or found in childhood to have 1 degenerate ovary and 1 testis. Lange et al. (2009) observed that the average intercentromeric distance in the feminized individuals was twice that in the males (p less than 10(-6)), supporting the hypothesis that mitotic instability and resultant XO mosaicism may cause sex reversal.
Using a human SRY probe, Foster et al. (1992) identified and cloned related genes from the Y chromosome of 2 marsupial species. Comparisons of eutherian ('placental') and metatherian (marsupial) Y-located SRY sequences suggested rapid evolution of these genes, especially outside the region encoding the DNA-binding 'high mobility group' domain (HMG box). The SRY homolog and the homolog of the mouse Ube1y were the first genes to be identified on the marsupial Y chromosome. Whitfield et al. (1993) and Tucker and Lundrigan (1993) likewise found that whereas the central 'high mobility group' domain of about 78 amino acids of the SRY protein is highly conserved, evolution in primates and in mice and rats has been rapid in the regions flanking the conserved domain. The high degree of sequence divergence and the frequency of nonsynonymous mutations suggested either that the majority of the coding sequence has no functional significance and therefore is not functionally constrained or that it has been subject to directional selection with species-specific adaptive divergence.
Foster and Graves (1994) identified a sequence on the marsupial X chromosome that shares homology with SRY and shows near-identity with the mouse and human SOX3 gene (313430; formerly called a3), the SOX gene most closely related to SRY. Foster and Graves (1994) suggested that the highly conserved X chromosome-linked SOX3 represents the ancestral SOX gene from which the sex-determining SRY gene was derived.
In therian mammals (placentals and marsupials), sex is determined by an XX female:XY male system in which the SRY gene on the Y chromosome affects male determination. Birds have a ZW female:ZZ male system with no homology with mammalian sex chromosomes. In birds, dosage of a Z-borne gene, possibly DMRT1 (602424), affects male determination. Platypus employ a sex-determining system of 5 X and 5 Y chromosomes. Females have 2 copies of the 5 Xs; males have 5X and 5Y chromosomes, which form an alternating XY chain during male meiosis. Veyrunes et al. (2008) found no homology between the 10 platypus sex chromosomes and the ancestral therian X chromosome, which is homologous to platypus chromosome 6. Orthologs of genes in the conserved region of human X (including SOX3, the gene from which SRY evolved) all map to platypus chromosome 6, which therefore represents the ancestral autosome from which the therian X and Y pair derived. The platypus X chromosomes have substantial homology with the bird Z chromosome (including DMRT1), and to segments syntenic with this region in the human genome. Veyrunes et al. (2008) concluded that the therian X and Y chromosomes, including the SRY gene, evolved from an autosomal pair after the divergence of monotremes only 166 million years ago.
Hughes et al. (2010) finished sequencing the male-specific region of the Y chromosome (MSY) in chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. Comparison of the MSYs of the 2 species showed that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. Hughes et al. (2010) suggested that the extraordinary divergence of the chimpanzee and human MSYs was driven by 4 synergistic factors: the prominent role of the MSY in sperm production, 'genetic hitchhiking' effects in the absence of meiotic crossingover, frequent ectopic recombination within the MSY, and species differences in mating behavior.
The human and mouse Sry genes share 89% amino acid identity in their HMG box domains, but they diverge significantly in their C termini. Coward et al. (1994) found that Sry alleles from all mouse strains examined encode a glutamine- and histidine-rich C-terminal domain. Sry alleles encoding a polyglutamine tract of either 13 or 11 glutamine residues were associated with partial (fetal) or complete sex reversal, respectively, when introduced on a C57BL/6J background. Alleles encoding a tract of 12 glutamine residues were not associated with sex reversal.
Only the HMG box region of the SRY gene has been conserved through evolution, suggesting that SRY function depends solely on the HMG box and therefore acts as an architectural transcription factor. In mice, SRY includes a large CAG trinucleotide repeat region encoding a C-terminal glutamine-rich domain that acts as a transcriptional trans-activator in vitro. The absence of this or any other potential trans-activating domain in other mammals, however, has raised doubts as to its biologic relevance. To test directly whether the glutamine-rich region is required for SRY function in vivo Bowles et al. (1999) created truncation mutations of the Mus musculus SRY gene and tested their ability to induce testis formation in XX embryos using a transgenic mouse assay. SRY constructs that encoded proteins lacking a glutamine-rich region were unable to effect male sex determination, in contrast to their wildtype counterparts. Bowles et al. (1999) concluded that the glutamine-rich repeat domain of the mouse SRY protein has an essential role in sex determination in vivo and that SRY may act via a fundamentally different biochemical mechanism in mice compared with other mammals.
Nef et al. (2003) demonstrated that the insulin receptor tyrosine kinase family, comprising INSR (147670), IGF1R (147370), and IRR (147671), is required for the appearance of male gonads and thus for male sexual differentiation in mice. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry and the early testis-specific marker Sox9 (608160) indicated that the insulin signaling pathway is required for male sex determination.
In 6 sterile heifers that were female in appearance and in genital organs, Kawakura et al. (1996) found that blood, skin, spleen, and kidney showed a normal male 60,XY karyotype. Although the SRY gene was detected by PCR in normal bull, it was not detected in normal cow or in 3 60,XY female bovine cases studied.
Using transcription activator-like effector nuclease (TALEN) technology, Kato et al. (2013) created an Sry-knockout XY mouse, which displayed sex reversal. The knockout mice had female external and internal genitalia, wildtype female levels of blood testosterone, and largely female sexually dimorphic nucleus of medial preoptic area of the brain. Mutant mice exhibited a slightly lengthened estrous cycle and performed copulatory behavior as females, although they appeared to be infertile. Ovaries of the mutant mice had fewer developing follicles and were more luteinized that those of wildtype females, which may account for infertility in the Sry-knockout mouse.
Miyawaki et al. (2020) identified a cryptic second exon in the mouse Sry gene and a corresponding 2-exon Sry transcript that they designated SryT. XY mice lacking SryT only were sex-reversed, and ectopic expression of SryT in XX mice induced male development. SryT mRNA was expressed similarly to that of the canonical single-exon Sry transcript, which the authors called SryS, but the SryT protein was expressed predominantly due to the absence of a degron found at the C terminus of SryS. Sry exon 2 appeared to have evolved recently in mice through acquisition of a retrotransposon-derived coding sequence to replace the degron. Miyawaki et al. (2020) concluded that, in nature, SryT, and not SryS, is the bona fide testis-determining factor in mice.
DNA-binding proteins are typically involved in the developmental control of gene expression. High mobility group (HMG) proteins contain a DNA-binding motif called the HMG domain. They have been proposed to act either as target-specific transcription factors or as chromatin structure regulatory elements, or both. Jay et al. (1997) stated that more than 100 HMG-box containing proteins have been reported and classified into 2 distinct subgroups according to the sequence specificity of the DNA binding, the number of HMG DNA-binding domains, and phylogenetic considerations. The first subgroup comprises proteins that are all potential transcription factors believed to control gene expression during development. They contain only 1 DNA-binding domain and they bind to DNA in a sequence-specific fashion. The second subgroup consists of all other HMG box-containing proteins, most of which contain more than 1 DNA-binding domain and can bind to DNA in a non-sequence-specific manner. SRY belongs to the first subgroup. Its cloning led to the discovery of a family of both autosomal and X-linked genes called SOX (for 'SRY-box' related) because of the strong homology of their DNA-binding domain with the HMG box of SRY.
Page et al. (1987) cloned part or all of what they thought to be the TDF gene, found that some sequences were highly conserved in mammals and even birds, and showed that the nucleotide sequence of the conserved DNA codes for zinc finger domains. ZFY (zinc finger protein, Y-linked; 314980) was the designation approved by the HGM workshop committee, with ZFX being the X-linked counterpart. ZFY proved, however, not to be TDF (Palmer et al., 1989).
Jager et al. (1990) demonstrated a mutation in SRY in 1 of 12 sex-reversed XY females with gonadal dysgenesis (SRXY1; 400044) who had no large deletions of the short arm of the Y chromosome. They found a 4-bp deletion (nucleotides 773-776) in the part of the SRY gene that encodes a conserved DNA-binding motif. A frameshift presumably led to a nonfunctional protein. Mutation occurred de novo, because the father had a normal SRY sequence. This provided strong evidence that SRY is TDF. The de novo G-to-A mutation led to a change from methionine to isoleucine. Hawkins (1993) noted that the mutation is in the HMG box of SRY.
In an XY female with gonadal dysgenesis (SRXY1; 400044), her father, her 2 brothers and an uncle, Jager et al. (1992) found a T-to-C transition in the region of the SRY gene coding for a protein motif known as the high mobility group (HMG) box, a protein domain known to confer DNA-binding specificity on the SRY protein. The mutation resulted in the substitution, at amino acid position 109, of a serine residue for phenylalanine, a conserved aromatic residue in almost all HMG box motifs known. This F109S mutation was not found in 176 male controls. When recombinant wildtype SRY and SRY(F109S) mutant protein were tested in vitro for binding to the target site AAC AAAG, no differences in DNA-binding activity were observed. These results implied that the F109S mutation either is a rare neutral sequence variant, or produces an SRY protein with slightly altered in vivo activity, the resulting sex phenotype depending on the genetic background or environmental factors. The proband had primary amenorrhea and was 180 cm tall. Prior to therapy, mammary development was at stage III (Tanner). No signs of virilization were found. At laparotomy, bilateral streak gonads, atrophic fallopian tubes, and a rudimentary uterus with a narrow lumen were detected. Although the paternal uncle with the F109S mutation had an undescended right testis, the family was unremarkable with regard to infertility, gynecologic tumors, and abnormal sex phenotypes.
Vilain et al. (1992) described a family in which all 5 XY individuals in 2 generations had a single basepair substitution resulting in an amino acid change in the conserved domain of the SRY open reading frame. A G-to-C transversion at nucleotide 588 resulted in substitution of leucine for valine-60. Three of the individuals were XY sex-reversed females (SRXY1; 400044) and 2 were XY males. One of the males had 8 children; all were phenotypic females, including 2 who were sex-reversed XY females carrying the mutation mentioned. Several models were proposed to explain association between a sequence variant in SRY and 2 alternative sex phenotypes. These explanations included the existence of alleles at an unlinked locus.
McElreavey et al. (1992) described an XY sex-reversed female with pure gonadal dysgenesis (SRXY1; 400044) who harbored a de novo nonsense mutation in SRY, which resulted directly in the formation of a stop codon in the putative DNA-binding motif. A C-to-T transition at nucleotide 687 changed a glutamine codon (CAG) to a termination codon (TAG). The patient, referred to by the authors as the 'propositus,' was a phenotypic female who presented at age 20 years for primary amenorrhea. Treatment with estrogen induced menstruation and slight enlargement of the breasts which were underdeveloped. Laparotomy showed 2 streak gonads without germ cells or remnants of tubes.
In 'patient 213' (patient 4 in the report of Berkovitz et al., 1991), a phenotypic female with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; 400044), Hawkins et al. (1992) identified a C-G transversion at nucleotide 680, causing an isoleucine-to-methionine amino acid substitution within the HMG box. The father and brother of patient 213 also carried the mutation, which was not found in 78 ethnically matched unrelated males. The authors noted that in vitro studies by Harley et al. (1992) demonstrated that the I90M mutant had reduced DNA-binding activity.
Dork et al. (1998) observed this mutation in a patient unrelated to that reported by Hawkins et al. (1992). None of the previously reviewed mutations had been observed in more than a single family. In 3 cases, however, fertile fathers were found to share the same SRY mutation with their sex-reversed daughters (Berta et al., 1990; Jager et al., 1992; Vilain et al., 1992). In the absence of mosaicism, there are plausible explanations for these familiar variants. The variant could fortuitously occur in a family segregating for a different sex-reversing gene, or the variant may predispose toward sex reversal and cause a differentiation effect only in association with other genetic or environmental factors. In the case reported by Hawkins et al. (1992), I90M was likewise associated with complete gonadal dysgenesis in the proband but was also present in normal relatives of the patient, including the father. Thus, Dork et al. (1998) concluded that this appears to be an instance of a Y-linked inherited disorder with incomplete penetrance and suggested that identification of unrelated individuals carrying the I90M mutation may help to elucidate the mechanism.
Maier et al. (2003) reported a 46,XY true hermaphrodite (see 400044) who had the I90M mutation in the SRY gene. The father, 3 uncles, and an older brother carried the identical mutation without phenotypic effects. Maier et al. (2003) concluded that the mutated protein retained enough activity to allow normal development in some individuals.
In their 'patient 207' (patient 5 of Berkovitz et al., 1991) with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; 400044), Hawkins et al. (1992) identified an A-T transversion at nucleotide 727, resulting in a lysine-to-isoleucine substitution within the HMG box.
In their 'patient 208' (patient 6 of Berkovitz et al., 1991) with complete gonadal dysgenesis and a 46,XY karyotype (SRXY1; 400044), Hawkins et al. (1992) found deletion of nucleotide 734 causing a frameshift. The father and brother of patient 208 did not share the deletion, indicating that the mutation was de novo. Hawkins (1993) noted that the mutation is in the HMG box of SRY.
In a Chinese XY female with gonadal dysgenesis described as Swyer syndrome (SRXY1; 400044), Zeng et al. (1993) described a G-to-A transition in codon 113 resulting in a change from alanine to threonine. This residue lies within the putative DNA binding motif.
Iida et al. (1994) identified a single-basepair substitution within the HMG box of the SRY gene in a 28-year-old married Japanese woman with a history of primary amenorrhea and infertility. Physical examination showed an apparently normal female with a weight of 62 kg and a height of 170.5 cm. While the external genitalia were those of a female, they were infantile with no hypertrophy of the clitoris. The vagina was normal and a cervix was present. The uterus was normal in shape and position. Laboratory examination demonstrated that the amenorrhea was due to ovarian failure. There was no elevation of androgen levels. The karyotype was 46,XY (SRXY1; 400044). Both gonads were partially resected because of the risk of malignant development and showed fibroadipose tissue with no malignant cells and no ovarian or testicular components. By single-strand conformation polymorphism analysis followed by direct sequencing, Iida et al. (1994) demonstrated a GGT to GAT substitution in codon 107, counted from the initiation site of the gene, which predicted a change from a tryptophan residue to a termination codon.
This mutation, which caused sex reversal in a female patient with a 46,XY karyotype (SRXY1; 400044), was used by Haqq et al. (1994) to demonstrate that the structural interactions of the HMG box with DNA was altered to result in failure to induce transcription of the gene for mullerian inhibiting substance. The normal protein-DNA interaction consists of partial side chain intercalation into a widened minor groove.
Studying this same mutation, Peters et al. (1995) demonstrated that 2 DNA-binding activities of SRY could be distinguished. The sequence-specific recognition of duplex DNA must be required for male sex determination because it was eliminated by this mutation in the SRY HMG box. However, the sequence-independent binding to the sharp angles of 4-way DNA junctions was not affected.
In an XY female (SRXY1; 400044), Berta et al. (1990) identified a G-to-A transition in the SRY gene resulting in a change from methionine-64 to isoleucine. This residue lies within the HMG box. The mutation was presumed to be de novo because it was not found in the patient's father or brother.
In an XY female (SRXY1; 400044), Hawkins et al. (1992) identified a G-to-A transition at codon 70 of SRY which results in a stop codon at trp70. This residue lies within the HMG box.
In an XY female (SRXY1; 400044), Muller et al. (1992) identified an A-to-T transversion at codon 92 of the SRY gene which results in a stop codon at lys92. This residue lies within the HMG box.
In an XY female (SRXY1; 400044), Hawkins et al. (1992) identified a G-to-C transversion resulting in a change from glycine-95 to arginine. This residue lies within the HMG box.
Veitia et al. (1997) reported a T-to-A transversion occurring at nucleotide 12 in the SRY gene, resulting in a premature termination codon prior to the HMG box. This was a de novo substitution in a completely sex-reversed patient (SRXY1; 400044).
Veitia et al. (1997) found a de novo recurrence of the C-to-T transition which gave rise to the arg133trp mutation first reported by Affara et al. (1993). Both patients had pure gonadal dysgenesis (SRXY1; 400044). The arg at codon 133 was conserved in the SRY gene of all species studied at that time.
Brown et al. (1998) described a 28-year-old West Indian woman with the primary complaint of infertility. She reported menarche and normal breast development at age 13 to 14 years and had had regular monthly menses until age 17 years, when she electively began oral contraceptives, which she continued until age 25 years. Irregular menses resumed with the discontinuation of oral contraception and for the 2 subsequent years she attempted to become pregnant. She had been treated with clomiphene citrate for presumed anovulation. She appeared normally feminized, and her physical examination, including her gynecological examination, was entirely normal, except for the fact that she was 193 cm tall. Specifically, she was not hirsute and had no stigmata of Turner syndrome. Breasts and pubic hair were Tanner stage 4. A chromosome analysis showed a 46,XY karyotype (SRXY1; 400044). At laparoscopy, the gonads appeared to be white fibrous streaks and were removed without difficulty. Study of all cells failed to detect any with either 2 X chromosomes or without a Y chromosome. The excised gonad from the right side consisted entirely of fibroadipose tissue; the left gonad contained a small amount of ovarian stromal-like tissue. No follicles were seen; however, a cluster of tubular structures was present. Fibroblast-like cells cultured from both gonadal tissue samples also had a pure XY karyotype. Analysis of the SRY gene revealed a C-to-T transition in the second codon, predicted to create a stop codon (gln2ter). The same mutation was found in the gonads of each side. There was no evidence of mosaicism. The patient's father's SRY gene showed an entirely normal sequence. Paternity was proved by the expected segregation of polymorphic PCR-based markers.
A mouse with a heritable mutation in the testis-determining gene was described by Lovell-Badge and Robertson (1990). XY mice with this mutation are fertile females, although fertility is reduced and their ovaries fail early, a picture similar to that in the patient reported by Brown et al. (1998).
In 1 of 21 Brazilian patients with 46,XY sex reversal (SRXY1; 400044), Domenice et al. (1998) found a ser18-to-asn (S18N) missense mutation upstream of the 5-prime border of the HMG box of the SRY gene. The variant sequence was also found in DNA obtained from blood and sperm of his father and in blood cells of his normal brother. The S18N mutation was not found in 50 normal males, ruling out the possibility of a common polymorphism. The patient had been evaluated at 4 years of age for ambiguous genitalia, characterized by microphallus, perineal hypospadias, bifid scrotum, and a gonad in the left inguinal region. His basal serum testosterone level was 16 ng/dl rising to 189 ng/dl after hCG stimulation. Histologic study showed a right streak gonad, a left dysgenic testis, and the presence of both wolffian and mullerian ducts. His brother at 18 years of age had normal male external genitalia with complete development of secondary sexual characteristics. The father was a 43-year-old phenotypically normal male.
Canto et al. (2000) performed molecular studies of the SRY gene in 3 patients with an Ullrich-Turner syndrome (see 163950) phenotype and bilateral streaks; 2 were 45,X/46,XY mosaic, and the third had a Y marker chromosome. In 2 of the patients, the authors identified an S18N mutation in the 5-prime non-HMG box region in DNA from blood and both streaks. This mutation was not identified in 5 normal males. Sequencing of the DNA region was normal in the father and older brother of patient 1, demonstrating that in this patient the mutation was de novo. The authors concluded that the previous report of a 46,XY patient with partial gonadal dysgenesis and the same mutation indicates the probable existence of a hotspot in this region of the SRY gene and strengthens the possibility that all gonadal dysgeneses constitute a spectrum of the same disorder. They also pointed out that this single genetic abnormality can result in a wide range of phenotypic expression.
Schaffler et al. (2000) described a nonmosaic XY sex-reversed female with pure gonadal dysgenesis, including 46,XY karyotype, completely female external genitalia, normal mullerian ducts, absence of wolffian ducts, and streak gonads (SRXY1; 400044), who harbored a yolk-sac tumor and was referred for the assessment of primary amenorrhea. They identified a novel de novo mutation, a G-to-A transition at position 284 within the HMG box of the SRY gene, resulting in a gly95-to-glu substitution. This mutation was not detected in the patient's father or in her male sibs. The authors concluded that these data provide further evidence to support the functional importance of the putative DNA-binding activity of the SRY HMG box.
Jordan et al. (2002) reported an A-to-T transversion at nucleotide 380 (with respect to the initiation codon) in the SRY gene that resulted in a tyr127-to-phe (Y127F) substitution in the protein. This sequence variant was found not only in the XY female patient (SRXY1; 400044) but also in her father, a phenotypically normal male. However, the Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved TYR residue in the HMG box of SRY. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggested that the variant is a novel mutation with functional consequences. The authors concluded that this allelic SRY variant shared by both an affected female and her normal father emphasizes the importance of modifier genes in the sex determination pathway.
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