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DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study

BACKGROUND: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cogn...

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Autores principales: Lee, Richard S., Song, Sophia Q., Garrison-Desany, Henri M., Carey, Jenny L., Lasutschinkow, Patricia, Zabel, Andrew, Bressler, Joseph, Gropman, Andrea, Samango-Sprouse, Carole
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252231/
https://www.ncbi.nlm.nih.gov/pubmed/34210361
http://dx.doi.org/10.1186/s13148-021-01123-4
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author Lee, Richard S.
Song, Sophia Q.
Garrison-Desany, Henri M.
Carey, Jenny L.
Lasutschinkow, Patricia
Zabel, Andrew
Bressler, Joseph
Gropman, Andrea
Samango-Sprouse, Carole
author_facet Lee, Richard S.
Song, Sophia Q.
Garrison-Desany, Henri M.
Carey, Jenny L.
Lasutschinkow, Patricia
Zabel, Andrew
Bressler, Joseph
Gropman, Andrea
Samango-Sprouse, Carole
author_sort Lee, Richard S.
collection PubMed
description BACKGROUND: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes. RESULTS: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index. CONCLUSIONS: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-021-01123-4.
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spelling pubmed-82522312021-07-06 DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study Lee, Richard S. Song, Sophia Q. Garrison-Desany, Henri M. Carey, Jenny L. Lasutschinkow, Patricia Zabel, Andrew Bressler, Joseph Gropman, Andrea Samango-Sprouse, Carole Clin Epigenetics Research BACKGROUND: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes. RESULTS: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index. CONCLUSIONS: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-021-01123-4. BioMed Central 2021-07-01 /pmc/articles/PMC8252231/ /pubmed/34210361 http://dx.doi.org/10.1186/s13148-021-01123-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Lee, Richard S.
Song, Sophia Q.
Garrison-Desany, Henri M.
Carey, Jenny L.
Lasutschinkow, Patricia
Zabel, Andrew
Bressler, Joseph
Gropman, Andrea
Samango-Sprouse, Carole
DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study
title DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study
title_full DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study
title_fullStr DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study
title_full_unstemmed DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study
title_short DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study
title_sort dna methylation and behavioral dysfunction in males with 47,xxy and 49,xxxxy: a pilot study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252231/
https://www.ncbi.nlm.nih.gov/pubmed/34210361
http://dx.doi.org/10.1186/s13148-021-01123-4
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