MRC Human Genetics Unit
Medical Research Council Human Genetics Unit


New DNA replication link to microcephalic primordial dwarfism

Mutations in DNA replication gene, polymerase epsilon, lead to growth restriction, adrenal dysfunction and immunodeficiency: November 2018

Diagram of DNA-binding proteins in the replication machinery with highlighted links to known growth disorders
DNA-binding proteins in the replication machinery with highlighted links to known growth disorders. Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer (Replication Stress and Cancer, Gaillard H, García-Muse T & Aguilera A), copyright 2015

As the molecular basis for many individuals affected by microcephalic primordial dwarfism is unknown, researchers performed whole-genome sequencing studies, (supported in part by the Scottish Genomics Partnership), to identify further genes and facilitate more comprehensive diagnosis. This international collaboration identified mutations in polymerase epsilon (POLE) in some individuals with microcephalic primordial dwarfism.

The size of an organism is largely determined by the number of cells. To increase their number, each cell divides into two daughter cells, but first the DNA within the cell must replicate itself so that each new daughter cell contains the right amount of genetic material. POLE is one of the essential enzymes that performs this task.  The researchers found that when errors occur in the POLE gene, this results in a condition characterised by poor growth, bone changes, adrenal hormone insufficiency and difficulty with fighting off infection.  This is very similar to a disorder already characterised called IMAGe syndrome, caused by changes in the CDKN1C gene.  In addition, the clinical features of POLE-IMAGe individuals overlap with other genes involved in DNA replication.  This helps highlight key features of this group of disorders which will help clinicians diagnose them more readily. 

Growth problems are likely a consequence of the cells dividing at a slower rate during development as they are less efficient at replicating their DNA.  However, it is less clear why problems with DNA replication affect the development of specific hormone glands and the immune system. This work also raises the possibility that POLE and other genes causing IMAGe syndrome are linked by a common biological mechanism, one which warrants further investigation.


Andrew Jackson research group

Scottish Genomes Partnership

Original research article: