FEB 13, 2017 12:27 PM PST

New Gene Defect Identified That Leads to Microcephaly and Dwarfism

An international team of scientists has discovered a gene involved in DNA replication that when mutated has profound effects on growth and development, leading to microcephalies and dwarfism characteristics.

“Despite DNA replication being a process that is fundamental to life, there is still a lot we don't know. This research sheds new light on the mechanisms underlying DNA replication, and the effect on human health when this process goes wrong,” comments Professor Grant Stewart, from the Institute of Cancer and Genomic Sciences at the University of Birmingham and a leader in the study.

DNA replication fork structure

DNA replication is a very precise and regulated process within cells. Not only is every step carefully performed, but there are even more processes in place to ensure replication is completed correctly and efficiently. DNA repair processes, structure protection and restart mechanisms are available to fix any issues that arise.

The gene DONSON, a downstream neighbor of SON, has been identified as a primary player in DNA replication as a novel DNA replication fork stabilizer, protecting the structure during the addition of new DNA components. Loss of function mutations in DONSON can lead to severe DNA damage due to cleavage of stalled replication forks. In addition, the mutations affect a cell’s ability to initiate signaling mechanisms in response to stress and damage during replication, which can result in further impaired checkpoint processes and general chromosome instability.

The study, published in Nature Genetics, analyzed the genomes of more than 250 patients with microcephalic dwarfism, characterized by short stature and small head size. The analysis revealed that 29 of the patients had mutations in DONSON and that these mutations seemed to be the primary cause of their afflictions. Further study of cells grown in the lab with the mutations and of the gene’s protein profile showed that the impaired DONSON gene can lead to growth defects typical of microcephalic dwarfism.

“Identification of DONSON as a microcephaly gene has given us new insights into how the genome is protected during DNA replication,” says Professor Andrew Jackson, of the University of Edinburgh's Institute for Genetics and Molecular Medicine and co-author on the study.

The findings offer expanded potential for more accurate diagnoses of genetic microcephaly in certain circumstances. The study also provides more insight into the basic biology of replication and its far-reaching effects on growth and development.

Professor Christopher Mathew, from the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' and King's College London and co-author on the study, explains, “This is a good example of how unravelling the genetics of rare human disorders can provide profound insight into basic biological processes.”

Sources: Nature Genetics, Scienmag

About the Author
  • I love all things science and am passionate about bringing science to the public through writing. With an M.S. in Genetics and experience in cancer research, marketing and technical writing, it is a pleasure to share the latest trends and findings in science on LabRoots.
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