science
Study Links DNMT3A Mutations to Accelerated Aging Features
Researchers examined Heyn–Sproul–Jackson syndrome caused by DNMT3A gain-of-function mutations. The mutations produced DNA hypermethylation that impaired adult stem cell function and produced age-related changes in blood, bone, and metabolic tissues in both humans and mice.
Jun 12, 6:11 PM·1m read1 source
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Researchers identified ten individuals with a median age of 11 years who carried these mutations and displayed features including alopecia, osteopenia, lymphopenia, and altered fat distribution. DNA methylation analysis showed increased methylation at Polycomb-marked regions in peripheral blood samples from affected individuals.
The same pattern of hypermethylation was observed in a mouse model carrying the equivalent mutation, and it accumulated over time in adult stem cells.
The study found reduced multilineage output from adult stem cells in both humans and mice. In one examined lineage, hypermethylation at the promoter of the Pax5 gene correlated with lower B-cell production, contributing to observed lymphopenia. Three older patients developed asymptomatic paragangliomas.
One patient died at age 7 from metastatic osteosarcoma, and another developed bone marrow failure in her twenties.
The findings indicate that DNA hypermethylation driven by DNMT3A gain-of-function mutations can impair stem cell function and produce specific age-related pathologies. The authors suggest these pathways may be relevant to future therapeutic approaches for hematological, skeletal, and metabolic conditions associated with aging.
