A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal

Bardoni, Barbara; Zanaria, Elena; Guioli, Silvana; Floridia, Giovanna; Worley, Kim C.; Tonini, G.; Ferrante, Emanuele; Chiumello, G; McCabe, Edward R.B.; Fraccaro, M.; Zuffardi, Orsetta; Camerino, Giovanna

doi:10.1038/ng0894-497

Cited by 613 publications

(271 citation statements)

References 17 publications

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“…2 The molecular characterisation of XY females has already led to the identification of several sex-determining genes in addition to the male dominator factor on the Y chromosome, SRY. 3 DAX1 in the dosage sensitive sex-reversal locus on the X, 4 the steroidogenic factor 1 (SF1) on 9q, 5 the SRY-related box gene 9 (SOX9) on 17q, 6,7 and the Wilms' tumor gene (WT1) on 11p. 8 However, mutations in these genes, which are required for normal gonadal development, have only been found in a relatively small number of sex-reversal cases, ie 15% of XY females show mutations in SRY.…”

Section: Introductionmentioning

confidence: 99%

FISH mapping of the sex-reversal region on human chromosome 9p in two XY females and in primates

et al. 2000

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Accumulating evidence suggests that haploinsufficiency of a dosage-sensitive gene(s) in human chromosome 9p24.3 is responsible for the failure of testicular development and feminisation in XY patients with monosomy for 9p. We have used molecular cytogenetic methods to characterise the sex-reversing 9p deletions in two XY females. Fluorescence in situ hybridisation (FISH) with YACs from the critical 9p region containing an evolutionarily conserved sex-determining gene, DMRT1, is a very fast and reliable assay for patient screening. Comparative YAC mapping on great ape and Old and New World monkey chromosomes demonstrated that the critical region was moved from an interstitial position on the ancestral primate chromosome to a very subtelomeric position in chimpanzee and humans by a pericentric inversion(s). Pathological 9p rearrangements may be the consequence of an evolutionary chromosome breakpoint in close proximity to the sex-reversal region.

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Section: Introductionmentioning

confidence: 99%

FISH mapping of the sex-reversal region on human chromosome 9p in two XY females and in primates

et al. 2000

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“…Under the influence of a Y chromosome, probably also an X chromosome and some genetic sites such as WT-1, SF-1, SOX-9 and DAX-1 genes located on autosomal or X chromosomes, testicular differentiation occurs between the sixth and eighth weeks of gestational age. [3][4][5][6] By the eighth week, the developing testis begins to secrete two hormones, namely testosterone and müllerian inhibiting substance (MIS). Testosterone is produced by Leydig cells and stimulates virilization of the ipsilateral Wolffian duct into epididymis, vas and seminal vesicles, while MIS, produced by the Sertoli cells, causes the müllerian ducts to reabsorb.…”

Section: Discussionmentioning

confidence: 99%

Report of a 45, X male with monoorchism and distal hypospadias

Zhou

2001

Int J of Urology

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We present the rare case of a 5-year-old boy with a 45, X karyotype. The boy's family pedigree analysis was unremarkable. On admission, he was 97.4 cm tall (2.0 SD below normal references) and weighed 13.9 kg (1.0 SD below normal references). Mild mental retardation was suspected on the PPVT scale. Physical examination revealed a well-developed penis with subglanular hypospadias. His left testis was located well down at the bottom of the scrotum and the right testis was impalpable.Unilateral testicular agenesis and persistence of müllerian remnants within the hernia sac were noted on the previous records of inguinal exploration on the right side. The left testis was biopsied through a scrotal incision and prepubertal testicular tissue was confirmed. No ovary was found on laparotomy exploration. Hypospadias was repaired with meatal advancement and glanuloplasty (MAGPI) urethroplasty. His postoperative course was uneventful. Our report represents a rare case of a boy with a 45, X karyotype. Current theories for testicular development were reviewed.

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“…In fact large Xp duplications do not have any influence on female fertility, as demonstrated by the mothers of XY patients with sex reversal due to Xp21 duplication. [26][27][28][29][30] Another patient with amenorrhea and a rearrangement similar to those of class II has been reported. 31 It is of interest to note that this patient, as cases 3-4, is taller than average, or at least than expected from her mid-parental height.…”

Section: Discussionmentioning

confidence: 99%

Opposite deletions/duplications of the X chromosome: two novel reciprocal rearrangements

et al. 2000

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Paralogous sequences on the same chromosome allow refolding of the chromosome into itself and homologous recombination. Recombinant chromosomes have microscopic or submicroscopic rearrangements according to the distance between repeats. Examples are the submicroscopic inversions of factor VIII, of the IDS gene and of the FLN1/emerin region, all resulting from misalignment of inverted repeats, and double recombination. Most of these inversions are of paternal origin possibly because the X chromosome at male meiosis is free to refold into itself for most of its length. We report on two de novo rearrangements of the X chromosome found in four hypogonadic females. Two of them had an X chromosome deleted for most of Xp and duplicated for a portion of Xq and two had the opposite rearrangement (class I and class II rearrangements, respectively). The breakpoints were defined at the level of contiguous YACs. The same Xp11.23 breakpoint was found in the four cases. That of the long arm coincided in three cases (Xq21.3) and was more proximal in case 4 (Xq21.1). Thus class I rearrangements (cases 1 and 2) are reciprocal to that of case 3, whilst that of case 4 shares only the Xp breakpoint. The abnormal X was paternal in the three cases investigated. Repeated inverted sequences located at the breakpoints of rearrangements are likely to favour the refolding of the paternal X chromosome and the recombination of the repeats. The repeat at the Xp11 may synapse with either that at Xq21.3 or that at Xq21.1. These rearrangements seem to originate as the Xq28 submicroscopic inversions but they are identifiable at the microscopic level and result from a single recombination event.

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A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal

Cited by 613 publications

References 17 publications

FISH mapping of the sex-reversal region on human chromosome 9p in two XY females and in primates

FISH mapping of the sex-reversal region on human chromosome 9p in two XY females and in primates

Report of a 45, X male with monoorchism and distal hypospadias

Opposite deletions/duplications of the X chromosome: two novel reciprocal rearrangements

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