Scientists have pieced together a molecular process that is disrupted in a rare genetic disorder called ICF syndrome, short for immunodeficiency-centromeric instability-facial anomalies. The condition is marked by an impaired immune system, distinctive facial features, and abnormal chromosomes.
In a new study, researchers in Hironori Funabiki’s lab and colleagues elsewhere examined a molecular pathway that adds chemical tags known as methyl groups to DNA. Methylation, which regulates genetic activity and prevents errors, becomes defective in ICF syndrome; particular areas on patients’ chromosomes lack these tags. Disrupted methylation, and other characteristics of the disease, have been linked to mutations in four proteins, but scientists didn’t understand how all these proteins work together in healthy cells.
Christopher Jenness, a graduate student in the lab, and his colleagues first revealed the function of one of these proteins, CDCA7. The scientists discovered that CDCA7 activates another protein called HELLS, and the protein pair then manipulates DNA so it can be methylated (without such manipulation, the majority of DNA in human chromosomes is not readily accessible for methylation). They were then able to determine the sequence by which HELLS, CDCA7, and the other two proteins methylate DNA—an important step toward understanding what goes wrong in the disease. Their work appears in the Proceedings of the National Academy of Sciences.