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M Sakaizumi - One of the best experts on this subject based on the ideXlab platform.
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Inherited XX Sex Reversal originating from wild medaka populations
Heredity, 2010Co-Authors: A Shinomiya, H Otake, S Hamaguchi, M SakaizumiAbstract:The teleost fish, medaka ( Oryzias latipes ), has an XX/XY Sex-determining mechanism. A Y-linked DM domain gene, DMY , has been isolated by positional cloning as the Sex-determining gene in this species. Previously, we conducted a field survey of genotypic Sex and found that approximately 1% of wild medaka are Sex-reversed (XX males and XY females). Here, we performed genetic analyses of nine spontaneous XX Sex-reversed males to elucidate its genetic basis. In all cases, the F_1 progeny were all females, whereas XX males reappeared in the backcross (BC) progeny, suggesting that XX Sex Reversal is a recessive trait. Although the incidences of Sex Reversal in the BC progeny were mostly low, 40% were males derived from one XX male. We performed linkage analysis using 55 BC males and located a single major factor, sda-1 ( s ex- d etermining a utosomal factor-1), controlling Sex Reversal in an autosomal linkage group. Thus, genes involved in the Sex-determining pathway can be isolated from spontaneous mutants in wild populations.
Gerd Scherer - One of the best experts on this subject based on the ideXlab platform.
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FGFR2 mutation in 46,XY Sex Reversal with craniosynostosis
Human Molecular Genetics, 2015Co-Authors: Stefan Bagheri-fam, Makoto Ono, Liang Zhao, Janelle Ryan, Raymond Lai, Yukako Katsura, Fernando J. Rossello, Peter Koopman, Gerd SchererAbstract:Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female Sex Reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female Sex Reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the 'knock-in' Crouzon mouse model Fgfr2c(C342Y/C342Y) carrying a Cys342Tyr substitution displays XY gonadal Sex Reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by Sex Reversal in Fgfr2c(C342Y/-) mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination.
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homozygous inactivation of sox9 causes complete xy Sex Reversal in mice
Biology of Reproduction, 2006Co-Authors: Francisco J Barrionuevo, Stefan Bagherifam, Jurgen Klattig, Ralf Kist, Makoto Mark Taketo, Christoph Englert, Gerd SchererAbstract:In the presence of the Y-chromosomal gene Sry, the bipotential mouse gonads develop as testes rather than as ovaries. The autosomal gene Sox9, a likely and possibly direct Sry target, can induce testis development in the absence of Sry. Sox9 is thus sufficient but not necessarily essential for testis induction. Mutational inactivation of one allele of SOX9/Sox9 causes Sex Reversal in humans but not in mice. Because Sox9 –/– embryos die around Embryonic Day 11.5 (E11.5) at the onset of testicular morphogenesis, differentiation of the mutant XY gonad can be analyzed only ex vivo in organ culture. We have therefore conditionally inactivated both Sox9 alleles in the gonadal anlagen using the CRE/loxP recombination system, whereby CRE recombinase is under control of the cytokeratin 19 promoter. Analysis of resulting Sox9 –/– XY gonads up to E15.5 reveals immediate, complete Sex Reversal, as shown by expression of the early ovary-specific markers Wnt4 and Foxl2 and by lack of testis cord and Leydig cell formation. Sry expression in mutant XY gonads indicates that downregulation of Wnt4 and Foxl2 is dependent on Sox9 rather than on Sry. Our results provide in vivo proof that, in contrast to the situation in humans, complete XY Sex Reversal in mice requires inactivation of both Sox9 alleles and that Sox9 is essential for testogenesis in mice. developmental biology, gene regulation, ovary, Sertoli cells, testis
Gary D. Berkovitz - One of the best experts on this subject based on the ideXlab platform.
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46 xx Sex Reversal with partial duplication of chromosome arm 22q
American Journal of Medical Genetics Part A, 2004Co-Authors: Tossaporn Seeherunvong, Erasmo M Perera, Adelaida Benigno, Roger P Donahue, Paul J. Benke, Gary D. BerkovitzAbstract:We present a case of 46,XX Sex Reversal in the absence of SRY but with partial duplication of chromosome 22q. The subject had multiple congenital anomalies but nearly complete masculinization of the external genitalia. Our case along with a previous case supports the existence of a gene on chromosome 22q that can trigger testis determination in the absence of SRY. We proposed that overexpression of the SOX10 gene at 22q13 might be the cause of Sex Reversal. We investigated 13 additional subjects with SRY-negative 46,XX Sex Reversal for microduplication of chromosome arm 22q in the region of SOX10 gene, but could not find evidence for it.
A Shinomiya - One of the best experts on this subject based on the ideXlab platform.
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Inherited XX Sex Reversal originating from wild medaka populations
Heredity, 2010Co-Authors: A Shinomiya, H Otake, S Hamaguchi, M SakaizumiAbstract:The teleost fish, medaka ( Oryzias latipes ), has an XX/XY Sex-determining mechanism. A Y-linked DM domain gene, DMY , has been isolated by positional cloning as the Sex-determining gene in this species. Previously, we conducted a field survey of genotypic Sex and found that approximately 1% of wild medaka are Sex-reversed (XX males and XY females). Here, we performed genetic analyses of nine spontaneous XX Sex-reversed males to elucidate its genetic basis. In all cases, the F_1 progeny were all females, whereas XX males reappeared in the backcross (BC) progeny, suggesting that XX Sex Reversal is a recessive trait. Although the incidences of Sex Reversal in the BC progeny were mostly low, 40% were males derived from one XX male. We performed linkage analysis using 55 BC males and located a single major factor, sda-1 ( s ex- d etermining a utosomal factor-1), controlling Sex Reversal in an autosomal linkage group. Thus, genes involved in the Sex-determining pathway can be isolated from spontaneous mutants in wild populations.
Vicki N. Meyers-wallen - One of the best experts on this subject based on the ideXlab platform.
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Exclusion of Candidate Genes for Canine SRY-Negative XX Sex Reversal
Journal of Heredity, 2005Co-Authors: Kumar S.d. Kothapalli, E. Kirkness, S. Pujar, R. H. Van Wormer, Vicki N. Meyers-wallenAbstract:In mammals, the Y-linked SRY gene is normally responsible for testis induction, yet testis development can occur in the absence of Y-linked genes, including SRY. The canine model of SRY-negative XX Sex Reversal could lead to the discovery of novel genes in the mammalian Sex determination pathway. The autosomal genes causing testis induction in this disorder in dogs, humans, pigs, and horses are presently unknown. In goats, a large deletion is responsible for Sex Reversal linked to the polled (hornless) phenotype. However, this region has been excluded as being causative of the canine disorder, as have WT1 and DMRT1 in more recent studies. The purpose of this study was to determine whether microsatellite marker alleles near or within five candidate genes (GATA4, FOG2, LHX1, SF1, SOX9) are associated with the affected phenotype in a pedigree of canine SRY-negative XX Sex Reversal. Primer sequences flanking nucleotide repeats were designed within genomic sequences of canine candidate gene homologues. Fluorescence-labeled polymorphic markers were used to screen a subset of the multigenerational pedigree, and marker alleles were determined by software. Our results indicate that the mutation causing canine SRY-negative XX Sex Reversal in this pedigree is unlikely to be located in regions containing these candidates.
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Sry-Negative XX Sex Reversal in the German Shorthaired Pointer Dog
Journal of Heredity, 1995Co-Authors: Vicki N. Meyers-wallen, L. Bowman, Gregory M. Acland, V. L. Palmer, D. Schlafer, Virginia R. FajtAbstract:Present hypotheses indicate that a testis differentiation cascade in mammals is induced by Sry, a gene encoding a DNA binding protein of the high mobility group (HMG) class. In XX Sex Reversal, individuals lacking a Y chromosome develop testicular tissue. Sry translocation from the Y to the X chromosome has been found in some, but not all, of these individuals. XX Sex Reversal in the German shorthaired pointer dog may be a model of Sry-negative XX Sex Reversal in humans. The purposes of this study were to report the familial occurrence of Sex Reversal and determine whether the conserved Sry HMG box, the region of the Sry protein essential for testis induction, is present in genomic DNA of affected dogs. Canine Sry HMG box sequences were used as primers in polymerase chain reactions. A 104 bp Sry HMG box product was generated from normal males, but not from females or XX Sex reversed dogs. Parallel control reactions using hypoxanthine phosphoribosyl transferase primers generated a 177 bp product from all dogs. The pedigree of affected dogs and the absence of Sry HMG box sequences in their genomic DNA suggest that this disorder is due to a mutant autosomal gene in the testis differentiation cascade.
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XX Sex Reversal in a llama.
Journal of the American Veterinary Medical Association, 1994Co-Authors: C. E. Wilker, Vicki N. Meyers-wallen, Donald H. Schlafer, Nathan L. Dykes, András Kovács, Barry A. BallAbstract:A 5-month-old llama was examined for evaluation of Sexually ambiguous external genitalia. To determine the phenotypic, chromosomal, and gonadal Sex of the llama, transrectal palpation and ultrasonography, contrast cystography, karyotype evaluation, laparoscopy, and necropsy were performed. A karyotype of 74,XX and finding of components of the mullerian duct system were suggestive of a female phenotype and chromosomal Sex. On histologic evaluation, however, components of the wolffian duct system also were found, and the gonads were composed entirely of testicular tissue. The diagnosis was XX Sex Reversal, with a XX male phenotype.
