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      Similar Cause, Different Phenotype: SOX9 Enhancer Duplication in a Family

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          Introduction: 46,XX ovotesticular disorder of sex development (DSD), as defined by the Chicago consensus in 2006, is characterized by histologically confirmed testicular and ovarian tissue in an individual with a 46,XX karyotype and a wide phenotypic spectrum from female to male appearance. Case Presentation: We report the case of two 46,XX sex determining region Y ( SRY) gene-negative siblings and their 46,XY father with an approximately 150 kilobase pair (kbp) duplication upstream of SOX9 ( SRY-box 9) gene’s transcriptional start site on chromosome 17 (chr17), which involved SOX9’s minimal critical 46,XX sex reversal region. This duplication is sufficient to trigger male development in the absence of Y-chromosomal material and can lead to various degrees of masculinization in 46,XX individuals by overexpression of SOX9. Based on anamnestic information and pedigree analysis, another possible carrier of this copy number variation (CNV) could have been the father’s sister. Discussion: By comparing the duplications of our two sibling patients and previously reported similar cases, we suggest that the small differences between their breakpoints could alternatively modify the inner structure and functioning of SOX9’stopologically associated domain (TAD) due to the differing fine TAD arrangements. Our data support the phenotypic modularity impact – incomplete penetrance and variable expressivity – of very similar but non-identical CNVs, which are possibly inherited across three generations.

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          Most cited references 13

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          ChIP-seq accurately predicts tissue-specific activity of enhancers.

          A major yet unresolved quest in decoding the human genome is the identification of the regulatory sequences that control the spatial and temporal expression of genes. Distant-acting transcriptional enhancers are particularly challenging to uncover because they are scattered among the vast non-coding portion of the genome. Evolutionary sequence constraint can facilitate the discovery of enhancers, but fails to predict when and where they are active in vivo. Here we present the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and map several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain and limb tissue. We tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. Our results indicate that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggest that such data sets will be useful to study the role of tissue-specific enhancers in human biology and disease on a genome-wide scale.
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            Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor.

            The growth-controlling functions of the adenovirus E1A oncoprotein depend on its ability ot interact with a set of cellular proteins. Among these are the retinoblastoma protein, p107, p130, and p300. We have isolated a cDNA encoding full-length human p300 and mapped the chromosomal location of the gene to chromosome 22q13. p300 contains three cysteine- and histidine-rich regions of which the most carboxy-terminal region interacts specifically with E1A. In its center, p300 contains a bromodomain, a hallmark of certain transcriptional coactivators. We have examined the ability of p300 to overcome the repressive effect of E1A on the SV40 enhancer. We show that p300 molecules lacking an intact E1A-binding site can bypass E1A repression and restore to a significant extent the activity of the SV40 enhancer, even in the presence of high levels of E1A protein. These results imply that p300 may function as a transcriptional adaptor protein for certain complex transcriptional regulatory elements.
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              Enhancer biology and enhanceropathies.

              Enhancers are cis-regulatory elements that enable precise spatiotemporal patterns of gene expression during development and are notable for being able to function at large distances from their target genes. Such regulatory elements often bypass intervening genes and typically comprise binding sites for multiple transcription factors that can also be transcribed by RNA polymerase II (Pol II) to produce noncoding enhancer RNAs (eRNAs). Genome-wide analyses have revealed chromatin signatures of enhancers, such as the enrichment for monomethylation of histone H3 lysine 4 (H3K4me1) and the acetylation or methylation of histone H3 lysine 27 (H3K27). Enhancer signatures have been used to describe the transitions of these regulatory elements from inactive to primed and from activated to decommissioned states during development. New mutations of enhancer sequences and of the protein factors regulating enhancer function in human disease continue to be identified, contributing to a growing class of 'enhanceropathies'.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                April 2020
                29 October 2019
                : 92
                : 5
                : 335-339
                aII. Department of Pediatrics, Semmelweis University, Budapest, Hungary
                bI. Department of Internal Medicine, Semmelweis University, Budapest, Hungary
                cI. Department of Pediatrics, Semmelweis University, Budapest, Hungary
                dDepartment of Molecular Genetics and Diagnostics, National Institute of Environmental Health, Budapest, Hungary
                Author notes
                *Eva Pinti, II. Department of Pediatrics, Semmelweis University, PF: 2., HU–1428 Budapest (Hungary), E-Mail pinti.eva@med.semmelweis-univ.hu
                503299 Horm Res Paediatr 2019;92:335–339
                © 2019 S. Karger AG, Basel

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                Tables: 1, Pages: 5
                Novel Insights from Clinical Practice / Case Report


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