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Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y(POS) mouse model
BACKGROUND: Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789682/ https://www.ncbi.nlm.nih.gov/pubmed/29378665 http://dx.doi.org/10.1186/s13293-018-0167-9 |
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author | Barseghyan, Hayk Symon, Aleisha Zadikyan, Mariam Almalvez, Miguel Segura, Eva E. Eskin, Ascia Bramble, Matthew S. Arboleda, Valerie A. Baxter, Ruth Nelson, Stanley F. Délot, Emmanuèle C. Harley, Vincent Vilain, Eric |
author_facet | Barseghyan, Hayk Symon, Aleisha Zadikyan, Mariam Almalvez, Miguel Segura, Eva E. Eskin, Ascia Bramble, Matthew S. Arboleda, Valerie A. Baxter, Ruth Nelson, Stanley F. Délot, Emmanuèle C. Harley, Vincent Vilain, Eric |
author_sort | Barseghyan, Hayk |
collection | PubMed |
description | BACKGROUND: Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more than half of the cases, a large number of variants of unknown clinical significance (VUS) were identified in those exomes. METHODS: To investigate the relevance of these VUS in regards to the patient’s phenotype, we utilized a mouse model in which the presence of a Y chromosome from the poschiavinus strain (Y(POS)) on a C57BL/6J (B6) background results in XY undervirilization and sex reversal, a phenotype characteristic to a large subset of human 46,XY DSD cases. We assessed gene expression differences between B6-Y(B6) and undervirilized B6-Y(POS) gonads at E11.5 and identified 515 differentially expressed genes (308 underexpressed and 207 overexpressed in B6-Y(POS) males). RESULTS: We identified 15 novel candidate genes potentially involved in 46,XY DSD pathogenesis by filtering the list of human VUS-carrying genes provided by exome sequencing with the list of differentially expressed genes from B6-Y(POS) mouse model. Additionally, we identified that 7 of the 15 candidate genes were significantly underexpressed in the XY gonads of mice with suppressed Sox9 expression in Sertoli cells suggesting that some of the candidate genes may be downstream of a well-known sex determining gene, Sox9. CONCLUSION: The use of a DSD-specific animal model improves variant interpretation by correlating human sequence variants with transcriptome variation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13293-018-0167-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5789682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57896822018-02-08 Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y(POS) mouse model Barseghyan, Hayk Symon, Aleisha Zadikyan, Mariam Almalvez, Miguel Segura, Eva E. Eskin, Ascia Bramble, Matthew S. Arboleda, Valerie A. Baxter, Ruth Nelson, Stanley F. Délot, Emmanuèle C. Harley, Vincent Vilain, Eric Biol Sex Differ Research BACKGROUND: Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more than half of the cases, a large number of variants of unknown clinical significance (VUS) were identified in those exomes. METHODS: To investigate the relevance of these VUS in regards to the patient’s phenotype, we utilized a mouse model in which the presence of a Y chromosome from the poschiavinus strain (Y(POS)) on a C57BL/6J (B6) background results in XY undervirilization and sex reversal, a phenotype characteristic to a large subset of human 46,XY DSD cases. We assessed gene expression differences between B6-Y(B6) and undervirilized B6-Y(POS) gonads at E11.5 and identified 515 differentially expressed genes (308 underexpressed and 207 overexpressed in B6-Y(POS) males). RESULTS: We identified 15 novel candidate genes potentially involved in 46,XY DSD pathogenesis by filtering the list of human VUS-carrying genes provided by exome sequencing with the list of differentially expressed genes from B6-Y(POS) mouse model. Additionally, we identified that 7 of the 15 candidate genes were significantly underexpressed in the XY gonads of mice with suppressed Sox9 expression in Sertoli cells suggesting that some of the candidate genes may be downstream of a well-known sex determining gene, Sox9. CONCLUSION: The use of a DSD-specific animal model improves variant interpretation by correlating human sequence variants with transcriptome variation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13293-018-0167-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-01-30 /pmc/articles/PMC5789682/ /pubmed/29378665 http://dx.doi.org/10.1186/s13293-018-0167-9 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Barseghyan, Hayk Symon, Aleisha Zadikyan, Mariam Almalvez, Miguel Segura, Eva E. Eskin, Ascia Bramble, Matthew S. Arboleda, Valerie A. Baxter, Ruth Nelson, Stanley F. Délot, Emmanuèle C. Harley, Vincent Vilain, Eric Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y(POS) mouse model |
title | Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y(POS) mouse model |
title_full | Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y(POS) mouse model |
title_fullStr | Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y(POS) mouse model |
title_full_unstemmed | Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y(POS) mouse model |
title_short | Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y(POS) mouse model |
title_sort | identification of novel candidate genes for 46,xy disorders of sex development (dsd) using a c57bl/6j-y(pos) mouse model |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789682/ https://www.ncbi.nlm.nih.gov/pubmed/29378665 http://dx.doi.org/10.1186/s13293-018-0167-9 |
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