Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

Amanda M. Smith; Taylor A. LaValle; Marwan Shinawi; Sai M. Ramakrishnan; Haley J. Abel; Cheryl A. Hill; Nicole M. Kirkland; Michael P. Rettig; Nichole M. Helton; Sharon E. Heath; Francesca Ferraro; David Y. Chen; Sangeeta Adak; Clay F. Semenkovich; Diana L. Christian; Jenna R. Martin; Harrison W. Gabel; Christopher A. Miller; Timothy J. Ley

doi:10.1038/s41467-021-24800-7

Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

Amanda M. Smith, Taylor A. LaValle, Marwan Shinawi, Sai M. Ramakrishnan, Haley J. Abel, Cheryl A. Hill, Nicole M. Kirkland, Michael P. Rettig, Nichole M. Helton, Sharon E. Heath, Francesca Ferraro, David Y. Chen, Sangeeta Adak, Clay F. Semenkovich, Diana L. Christian, Jenna R. Martin, Harrison W. Gabel, Christopher A. Miller, Timothy J. Ley

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3AOvergrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3A^R882H mutation. A germline mouse model expressing the homologous Dnmt3a^R878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.

Original language	English
Article number	4549
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24800-7
State	Published - Dec 1 2021

Access to Document

10.1038/s41467-021-24800-7

Cite this

Smith, A. M., LaValle, T. A., Shinawi, M., Ramakrishnan, S. M., Abel, H. J., Hill, C. A., Kirkland, N. M., Rettig, M. P., Helton, N. M., Heath, S. E., Ferraro, F., Chen, D. Y., Adak, S., Semenkovich, C. F., Christian, D. L., Martin, J. R., Gabel, H. W., Miller, C. A., & Ley, T. J. (2021). Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome. Nature communications, 12(1), Article 4549. https://doi.org/10.1038/s41467-021-24800-7

@article{6dce810aff504d95bc1ee00eb575a3ba,

title = "Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome",

abstract = "Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3AOvergrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3AR882H mutation. A germline mouse model expressing the homologous Dnmt3aR878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.",

author = "Smith, {Amanda M.} and LaValle, {Taylor A.} and Marwan Shinawi and Ramakrishnan, {Sai M.} and Abel, {Haley J.} and Hill, {Cheryl A.} and Kirkland, {Nicole M.} and Rettig, {Michael P.} and Helton, {Nichole M.} and Heath, {Sharon E.} and Francesca Ferraro and Chen, {David Y.} and Sangeeta Adak and Semenkovich, {Clay F.} and Christian, {Diana L.} and Martin, {Jenna R.} and Gabel, {Harrison W.} and Miller, {Christopher A.} and Ley, {Timothy J.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-24800-7",

language = "English",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

number = "1",

}

Smith, AM, LaValle, TA, Shinawi, M, Ramakrishnan, SM, Abel, HJ, Hill, CA, Kirkland, NM, Rettig, MP, Helton, NM, Heath, SE, Ferraro, F , Chen, DY , Adak, S , Semenkovich, CF, Christian, DL, Martin, JR, Gabel, HW , Miller, CA & Ley, TJ 2021, 'Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome', Nature communications, vol. 12, no. 1, 4549. https://doi.org/10.1038/s41467-021-24800-7

TY - JOUR

T1 - Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

AU - Smith, Amanda M.

AU - LaValle, Taylor A.

AU - Shinawi, Marwan

AU - Ramakrishnan, Sai M.

AU - Abel, Haley J.

AU - Hill, Cheryl A.

AU - Kirkland, Nicole M.

AU - Rettig, Michael P.

AU - Helton, Nichole M.

AU - Heath, Sharon E.

AU - Ferraro, Francesca

AU - Chen, David Y.

AU - Adak, Sangeeta

AU - Semenkovich, Clay F.

AU - Christian, Diana L.

AU - Martin, Jenna R.

AU - Gabel, Harrison W.

AU - Miller, Christopher A.

AU - Ley, Timothy J.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3AOvergrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3AR882H mutation. A germline mouse model expressing the homologous Dnmt3aR878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.

AB - Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3AOvergrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3AR882H mutation. A germline mouse model expressing the homologous Dnmt3aR878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.

UR - http://www.scopus.com/inward/record.url?scp=85111504241&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-24800-7

DO - 10.1038/s41467-021-24800-7

M3 - Article

C2 - 34315901

AN - SCOPUS:85111504241

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4549

ER -

Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

Abstract

Access to Document

Other files and links

Fingerprint

Cite this