A minority of 46,XX true hermaphrodites are positive for the Y-DNA sequence including SRY

McElreavey, Ken; Rappaport, R; Vilain, Éric; Abbas, Nacer; Richaud, F; Lortat-Jacob, S.; Berger, Roland; Leconiat, M; Boucekkine, C.; Kucheria, Kiran; Temtamy, Samia; Nihoul‐Feketé, Claire; Brauner, Raja; Fellous, Marc

doi:10.1007/bf00210754

Cited by 105 publications

(68 citation statements)

References 28 publications

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“…46,XX male syndrome is rare and its incidence is about 1:20000 in newborn males [2]. As far as the sexual phenotype is concerned, three clinical categories of sex-reversed 46,XX individuals have been identified: (1) Classic XX males, infertility with normal male internal and external genitalia; (2) XX males with ambiguous genitalia, usually detected at birth by external genital ambiguities such as hypospadias, micropenis, or hyperclitoridy; (3) XX true hermaphrodites, who carry internal or external genital ambiguities detected at birth [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Clinical, cytogenetic, and molecular analysis with 46,XX male sex reversal syndrome: case reports

Gao

Chen

Huang

et al. 2013

J Assist Reprod Genet

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Purpose To investigate the clinical characteristics of different categories of sex-reversed 46,XX individuals and their relationships with chromosomal karyotype and the SRY gene. Methods Chromosome karyotyping for peripheral blood culture and multi-PCR and FISH were performed. Results Endocrinological data showed that their endocrine hormone levels were similar to that observed for Klinefelter syndrome, with higher FSH and LH levels and lower T levels. Chromosome karyotyping for peripheral blood culture revealed 46, XX complement for 11 males. Molecular studies showed that there were locus deletions at SY84, SY86, SY127, SY134, SY254 and SY255 in AZF on chromosome Y in 9 cases, with the SRY gene present at the terminus of the X chromosome short arm. In one case, besides 6 locus deletions in AZF, there was also SRY gene deletion. In another case, there were locus deletions only at SY254 and SY255, with SY84, SY86, SY127 SY134 loci and SRY present. Conclusions The majority (10/11) of 46,XX males were SRY positive, with the SRY gene translocated into the terminus of the X chromosome short arm. These patients were caused mainly by an X/Y chromosomal inter-change during paternal meiosis, leading to the differentiation of primary gonads into testes. Only a single patient (1/11) was SRY-negative, in which there might be some unknown downstream genes involved in sex determination.

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Section: Introductionmentioning

confidence: 99%

Clinical, cytogenetic, and molecular analysis with 46,XX male sex reversal syndrome: case reports

Gao

Chen

Huang

et al. 2013

J Assist Reprod Genet

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“…Thirty-four sporadic cases have been analyzed; the majority have been previously published (21,22). They all carried internal or external genital ambiguities detected at birth.…”

Section: Introductionmentioning

confidence: 99%

A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development.

McElreavey

Vilain

Abbas

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

338

160

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The mammalian Y chromosome carries the SRY gene, which determines testis formation. Here we review data on individuals who are XX but exhibit male characteristics: some have SRY; others do not. We have analyzed three families containing more than one such individual and show that these individuals lack SRY. Pedigree analysis leads to the hypothesis that they carry recessive mutations (in a gene termed Z) that allow expression of male characteristics. We propose that wild-type Z product is a negative regulator ofmale sex determination and is functional in wild-type females. In males, SRY product represses or otherwise negatively regulates Z and thereby allows male sex determination. This hypothesis can also explain other types of sex reversal in mammals, in particular, XY females containing SRY. Some of these individuals may have mutations at the Z locus rendering them insensitive to SRY. Recessive mutations (such as the polled mutation ofgoats) leading to sex reversal are known in a variety of animals and might be used to map and ultimately clone the human Z gene.In mammals, male sex determination is controlled by the presence ofthe Y chromosome, which carries a gene encoding the testis-determining factor (TDF) on its short arm (1, 2). The current hypothesis for TDF action is that its product induces the testis-determination pathway, resulting ultimately in a male phenotype (1,(3)(4)(5)(6). Recently, the testis-determining factor gene has been isolated and named SR Y for sexdetermining region, Y chromosome (7). Genetic evidence to equate SRY and TDF comes from the study of XY sexreversed females who harbor de novo mutations in the SR Y open reading frame (ORF). The association of a de novo mutation in the SR Y ORF with a sex-reversed phenotype is consistent with SR Ybeing TDF (8-12). Further support for the role of SRY as the primary testis-determining factor comes from the observation that XX mice carrying the murine equivalent of SRY as a transgene develop as males (13).Mutations that cause sex reversal have proved to be important for identifying genes involved in sex determination in Drosophila, nematodes, and mice (5, 14 XX males with genital ambiguities: Sporadic andfamilial cases. Thirty-eight sporadic cases of XX males were analyzed for the presence of Y material (21). They were detected at birth because of external genital ambiguities, such as hypospadias (failure of urethra to close on the underside of the penis), micropenis, or hyperclitoridy. In all 38 cases, gonadal biopsy revealed the presence of bilateral testis. We also analyzed a familial case (family A) in which two children were XX males with ambiguities such as posterior hypospadias. As shown in Fig. 1, they have two normal brothers and five normal sisters. Both parents are normal; they are related by a first-cousin marriage.46,XX true hermaphrodites: Sporadic and familial cases. Thirty-four sporadic cases have been analyzed; the majority have been previously published (21,22). They all carried internal or external genital ambiguities ...

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“…In addition, most sex-reversed XY human females have a normal SRY gene and therefore must harbor mutations elsewhere in the sex-determining pathway (7). Normal male development in the absence of SRY in human XX males, in addition to two rodent species that lack Sry, suggests that the SRY gene acts only as a male switch and contributes little or nothing to male development itself.…”

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confidence: 99%

The human sex-reversing ATRX gene has a homologue on the marsupial Y chromosome, ATRY: Implications for the evolution of mammalian sex determination

Pask

Renfree

Graves

2000

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the ATRX gene on the human X chromosome cause X-linked ␣-thalassemia and mental retardation. XY patients with deletions or mutations in this gene display varying degrees of sex reversal, implicating ATRX in the development of the human testis. To explore further the role of ATRX in mammalian sex differentiation, the homologous gene was cloned and characterized in a marsupial. Surprisingly, active homologues of ATRX were detected on the marsupial Y as well as the X chromosome. The Y-borne copy (ATRY) displays testis-specific expression. This, as well as the sex reversal of ATRX patients, suggests that ATRY is involved in testis development in marsupials and may represent an ancestral testisdetermining mechanism that predated the evolution of SRY as the primary mammalian male sex-determining gene. There is no evidence for a Y-borne ATRX homologue in mouse or human, implying that this gene has been lost in eutherians and its role supplanted by the evolution of SRY from SOX3 as the dominant determiner of male differentiation.

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A minority of 46,XX true hermaphrodites are positive for the Y-DNA sequence including SRY

Cited by 105 publications

References 28 publications

Clinical, cytogenetic, and molecular analysis with 46,XX male sex reversal syndrome: case reports

Clinical, cytogenetic, and molecular analysis with 46,XX male sex reversal syndrome: case reports

A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development.

The human sex-reversing ATRX gene has a homologue on the marsupial Y chromosome, ATRY: Implications for the evolution of mammalian sex determination

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