Molecular Analysis of 9p Deletions Associated with XY Sex Reversal: Refining the Localization of a Sex-Determining Gene to the Tip of the Chromosome

Guioli, Silvana; Schmitt, Karin; Critcher, Ricky; Bouzyk, Mark; Spurr, Nigel K.; Ogata, Tsutomu; Hoo, Joe J.; Pinsky, Leonard; Gimelli, Giorgio; Pasztor, Linda M.; Goodfellow, Peter N.

doi:10.1086/302017

Cited by 60 publications

(45 citation statements)

References 15 publications

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“…[11][12][13][14][15][16] There is no correlation between the extent of sex reversal and the size of the del(9p). However, larger deletions leading to hemizygosity of many contiguous genes are associated with mental retardation and craniofacial abnormalities, in addition to partial or complete gonadal dysgenesis and ambiguous external and internal genitalia.…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of the distal short arm of chromosome 9p21-24 is associated with failure of the testicular development and XY feminisation. [11][12][13] The critical region for XY sex reversal has been narrowed down to band 9p24.3 and contains two candidate genes, DMRT1 (doublesex and mab-3 related transcription factor 1, formerly named DMT1) and DMRT2, which are expressed in the adult testis. Both DMRT1 and DMRT2 contain a DNA-binding DM domain and share significant structural homology with male sexual regulatory genes from Caenorhabditis elegans (mab-3) and Drosophila melanogaster (dsx).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

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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“…2) −/− males. Thus, the murine Dmrt1 null phenotype, like that of human 9p monosomy (Ogata et al 1997;Guioli et al 1998;Ion et al 1998;Veitia et al 1998), is a failure of testis differentiation, accompanied by germ cell death, rather than a transformation of testis to ovary. Although Dmrt1 mRNA is expressed in the XX genital ridge during early gonadal development, XX Dmrt1 +/− and Dmrt1 −/− mutant mice, like XX humans with 9p deletions, have normal ovaries and are fertile (data not shown).…”

Section: Dmrt1 Is Required For Testis But Not Ovary Differentiationmentioning

confidence: 99%

“…DM domain genes have been implicated in vertebrate sexual development by chromosomal location and by embryonic expression. Human DMRT1 maps to an autosomal locus (9p24.3) that, when hemizygous, is associated with defective testicular development and consequent 46,XY feminization (Crocker et al 1988;Hoo et al 1989;Bennett et al 1993;Veitia et al 1997Veitia et al , 1998Flejter et al 1998;Guioli et al 1998;Raymond et al 1998). In birds, which have ZZ/ZW sex determination, Dmrt1 is found on the Z chromosome (Nanda et al 1999), again suggesting that two doses of Dmrt1 (ZZ=male) might be necessary for testis development.…”

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confidence: 99%

Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation

Raymond¹,

Murphy²,

et al. 2000

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The only molecular similarity in sex determination found so far among phyla is between the Drosophila doublesex (dsx) and Caenorhabditis elegans mab-3 genes. dsx and mab-3 contain a zinc finger-like DNA-binding motif called the DM domain, perform several related regulatory functions, and are at least partially interchangeable in vivo. A DM domain gene called Dmrt1 has been implicated in male gonad development in a variety of vertebrates, on the basis of embryonic expression and chromosomal location. Such evidence is highly suggestive of a conserved role(s) for Dmrt1 in vertebrate sexual development, but there has been no functional analysis of this gene in any species. Here we show that murine Dmrt1 is essential for postnatal testis differentiation, with mutant phenotypes similar to those caused by human chromosome 9p deletions that remove the gene. As in the case of 9p deletions, Dmrt1 is dispensable for ovary development in the mouse. Thus, as in invertebrates, a DM domain gene regulates vertebrate male development.

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“…A gene termed DMRT1 (dsx-and mab3-related transcription factor 1) is located at the distal portion of chromosome 9p and this gene is deleted in the monosomy 9p syndrome that includes defective testis development and occasional male-to-female sex reversal [3][4][5]. The human DMRT1 gene shows significant molecular similarity to doublesex (dsx) (Drosophila) and mab-3 (Caenorhabditis elegans) [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional diversity of DMRT1 (dsx- and mab3-related transcription factor 1) in human testis

et al. 2006

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Recent advances in the evolutionary genetics of sex determination indicate that the only molecular similarity in sex determination found so far among phyla is between the fly doublesex, worm mab-3 and vertebrate DMRT1(dsx-and mab3-related transcription factor 1) /DMY genes. Each of these factors encodes a zinc-finger-like DNA-binding motif, DM domain. Insights into the evolution and functions of human DMRT1 gene could reveal evolutionary mechanisms of sexual development. Here we report the identification and characterization of multiple isoforms of human DMRT1 in the testis. These transcripts encode predicted proteins with 373, 275 and 175 amino acids and they were generated by alternative splicing at 3′ region. Expression level of DMRT1a is higher than those of both DMRT1b and c, and the DMRT1c expression was the lowest in testis, based on comparisons of mean values from real-time fluorescent quantitative RT-PCR analysis. Both DMRT1b and c result from exonization of intronic sequences, including the exonization of an Alu element. A further search for Alu elements within the DMRT1 gene demonstrated that all 99 Alu elements are non-randomly distributed among the non-coding regions on both directions. These new characteristics of DMRT1 would have an important impact on the evolution of sexual development mechanisms.

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Molecular Analysis of 9p Deletions Associated with XY Sex Reversal: Refining the Localization of a Sex-Determining Gene to the Tip of the Chromosome

Cited by 60 publications

References 15 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

Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation

Transcriptional diversity of DMRT1 (dsx- and mab3-related transcription factor 1) in human testis

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