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.
N1 - Funding Information:
The authors thank the TBRS Community, and especially Jill Kiernan and Kerry Grens, for help in identifying the subjects for this study, and the patients and families themselves for their participation. We also thank all referring physicians for providing records and obtaining blood samples for this study. This work was supported by an ASH Fellow to Faculty Award (AMS), NIH grants CA101937 and CA197561 (TJL), CA211782 (CAM), CA211466 (MPR), MH117405 (HWG), and the Barnes Jewish Hospital Foundation (TJL). We thank Dr. Eric Duncavage for providing Bethesda classifications for the mouse malignancies, Dr. David Wozniak for performing the animal behavioral studies, Ms. Mieke Hoock for excellent animal husbandry, and Drs. Olga Guryanova and Ross Levine for providing mice with the Lox-stop-Lox Dnmt3aR878H allele.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
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
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4549
ER -