In Tandem Intragenic Duplication of Doublesex and Mab-3-Related Transcription Factor 1 (DMRT1) in an SRY-Negative Boy with a 46,XX Disorder of Sex Development
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ABSTRACT:
SUBMITTER: Bertini V
PROVIDER: S-EPMC10671459 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:In most cases, male sexual differentiation occurs with SRY gene mediation. However, exceptional genotypes have been identified, as shown in this paper.
| S-EPMC7363349 | biostudies-literature
Project description:ContextThe genetic basis of human sex development is slowly being elucidated, and >40 different genetic causes of differences (or disorders) of sex development (DSDs) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available.ObjectiveWe used a targeted next-generation sequencing approach to analyze known and candidate genes for DSDs in individuals with no specific molecular diagnosis.Participants and designWe studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17β-hydroxysteroid dehydrogenase deficiency type 3, 5α-reductase deficiency type 2, and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis and those with a broad "partial androgen insensitivity syndrome" label. Targeted sequencing of 180 genes was undertaken.ResultsOverall, a likely genetic cause was found in 16 of 52 (30.8%) individuals (22.2% CGD, 40.0% pvDSD). Pathogenic variants were found in sex-determining region Y (SRY; n = 3), doublesex and mab-3-related transcription factor 1 (DMRT1; n = 1), NR5A1/steroidogenic factor-1 (SF-1) (n = 1), and desert hedgehog (DHH; n = 1) in the CGD group, and in NR5A1 (n = 5), DHH (n = 1), and DEAH-box helicase 37 (DHX37; n = 4) in the pvDSD group.ConclusionsReaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible.
| S-EPMC6855215 | biostudies-literature
Project description:Disorders of sex development (DSD) are a group of rare conditions characterized by discrepancy between chromosomal sex, gonads and external genitalia. Congenital abnormalities of the kidney and urinary tract are often associated with DSD, mostly in multiple malformation syndromes. We describe the case of an 11-year-old Caucasian boy, with right kidney hypoplasia and hypospadias. Genome-wide copy number variation (CNV) analysis revealed a unique duplication of about 550 kb on chromosome Xq27, and a 46,XX karyotype, consistent with a sex reversal phenotype. This region includes multiple genes, and, among these, SOX3 emerged as the main phenotypic driver. This is the fifth case reporting a genomic imbalance involving the SOX3 gene in a 46,XX SRY-negative male, and the first with associated renal malformations. Our data provide plausible links between SOX3 gene dosage and kidney malformations. It is noteworthy that the current and reported SOX3 gene duplications are below the detection threshold of standard karyotypes and were found only by analyzing CNVs using DNA microarrays. Therefore, all 46,XX SRY-negative males should be screened for SOX3 gene duplications with DNA microarrays.
| S-EPMC6714342 | biostudies-literature
Project description:Transforming growth factor beta receptor Ⅱ (TGFBR2), a core member of the transforming growth factor-β (TGF-β) signaling pathway. To date, chicken TGFBR2 (cTGFBR2) genomic structure has not been fully explored. Here, the complete sequences of cTGFBR2 transcript isoforms were determined by 5' and 3' rapid amplification of cDNA ends (5' & 3' RACE) and reverse transcription polymerase chain reaction (RT-PCR); the tissue expression profiling of cTGFBR2 transcript isoforms was performed using quantitative real-time polymerase chain reaction (qRT-PCR). The results showed that cTGFBR2 gene produced 3 transcript isoforms though alternative transcription initiation, splicing, and polyadenylation, which were designated as cTGFBR2-1, cTGFBR2-2, and cTGFBR2-3, respectively. These 3 cTGFBR2 transcript isoforms encoded 3 protein isoforms: cTGFBR2-1, cTGFBR2-2, and cTGFBR2-3. Duplication analysis revealed that, unlike other animal species, cTGFBR2 gene harbored a 5.5-kb intragenic tandem duplication. Tissue expression profiling in the 4-wk-old Arbor Acres (AA) broiler chickens showed that cTGFBR2-1 was ubiquitously expressed, with high expression in abdominal fat, subcutaneous fat, lung, gizzard, and muscle; cTGFBR2-2 was highly expressed in heart, kidney, gizzard, and muscle; cTGFBR2-3 was weakly expressed in all the tested chicken tissues. Tissue expression profiling in the 7-wk-old broiler chickens of the fat and lean lines of Northeast Agricultural University broiler lines divergently selected for abdominal fat content (NEAUHLF) showed that cTGFBR2-1 was significantly differentially expressed in all the tested tissues except heart, cTGFBR2-2 was significantly differentially expressed in all the tested tissues except subcutaneous fat and liver, and cTGFBR2-3 was significantly differentially expressed in all the tested tissues between the lean and fat lines. Intriguingly, in the fat line, the 3 cTGFBR2 transcript isoforms were expressed to varying degrees in all the 3 tested fat tissues, while in the lean line, only cTGFBR2-1 was expressed in all the 3 tested fat tissues. This is the first report of intragenic tandem duplication within TGFBR2 gene. Our findings pave the way for further studies on the functions and regulation of cTGFBR2 gene.
| S-EPMC9535321 | biostudies-literature
Project description:Impaired fertility associated with disorders of sex development (DSDs) due to genetic causes in dogs are more and more frequently reported. Affected dogs are usually of specific breeds thus representing a cause of economic losses for breeders. The aim of this research is to report the clinical, cytogenetic and molecular genetic findings of four XX SRY-negative DSD dog cases. All the subjects showed a female aspect and the presence of an enlarged clitoris with a penis bone. Morphopathological analyses performed in three of the four cases showed the presence of testes in two cases and ovotestis in another. Conventional and R-banded cytogenetic techniques were applied showing that no chromosome abnormalities were involved in these DSDs. CGH arrays show the presence of 11 copy number variations (CNVs), one of which is a duplication of 458 Kb comprising the genomic region between base 17,503,928 and base 17,962,221 of chromosome 9 (CanFam3 genome assembly). This CNV, confirmed also by qPCR, includes the promoter region of SOX9 gene and could explain the observed phenotype.
| S-EPMC7552623 | biostudies-literature
Project description:Knowing the factors responsible for sex determination in a species has significant theoretical and practical implications; the dmrt1 gene (Doublesex and Mab-3 (DM)-related Transcription factor 1) plays this role in diverse animal species. Solea senegalensis is a commercially important flat fish in which females grow 30% faster than males. It has 2n = 42 chromosomes and an XX / XY chromosome system for sex determination, without heteromorph chromosomes but with sex proto-chromosome. In the present study, we are providing the genomic structure and nucleotide sequence of dmrt1 gene obtained from cDNA from male and female adult gonads. A cDNA of 2027 containing an open-reading frame (ORF) of 1206 bp and encoding a 402 aa protein it is described for dmrt1 gene of S. senegalensis. Multiple mRNA isoforms indicating a high variable system of alternative splicing in the expression of dmrt1 of the sole in gonads were studied. None isoforms could be related to sex of individuals. The genomic structure of the dmrt1 of S. senegalensis showed a gene of 31400 bp composed of 7 exons and 6 introns. It contains an unexpected duplication of more than 10399 bp, involving part of the exon I, exons II and III and a SINE element found in the sequence that it is proposed as responsible for the duplication. A mature miRNA of 21 bp in length was localized at 336 bp from exon V. Protein-protein interacting networks of the dmrt1 gene showed matches with dmrt1 protein from Cynoglossus semilaevis and a protein interaction network with 11 nodes (dmrt1 plus 10 other proteins). The phylogenetic relationship of the dmrt1 gene in S. senegalensis is consistent with the evolutionary position of its species. The molecular characterization of this gene will enhance its functional analysis and the understanding of sex differentiation in Solea senegalensis and other flatfish.
| S-EPMC7605655 | biostudies-literature
Project description:Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. This study examines the result of conditional removal of Dmrt1 from Sertoli cells in P28 testis tissue.
2011-07-29 | GSE27261 | GEO
Project description:Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. This study examines the result of conditional removal of Dmrt1 in E15.5 ovaries.
2014-01-01 | GSE41896 | GEO
Project description:Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. This study examines the result of conditional removal of Dmrt1 in E15.5 testes tissue in B6 and 129Sv strains.
2014-01-01 | GSE41895 | GEO
Project description:Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. This study examines the result of conditional removal of Dmrt1 from Sertoli cells in P28 testis tissue. Testes from P28 Dmrt1 flox/flox mice were compared to testes from P28 Dmrt1 flox/flox mice with the Sertoli cell-specific Sf1 (Nr5a1; MGI:1346833) or Dhh (MGI:94891) promoters driving Cre expression.
2011-07-28 | E-GEOD-27261 | biostudies-arrayexpress