Mar 29, 2019 Well-studied gene implicated in rare syndrome

The gene CDC42 is implicated in a disease combination previously described in two other gene mutations

The patient had fewer larger platelets than is normal, yet unusually did not have a tendency to bleed

Reproduced with permission from reference 1 © 2015 Wiley Periodicals, Inc

DNA analyses on an 18-year-old girl with developmental delay and persistent low platelet count led to the identification of a new1 causative gene for this disease combination in 2015. A third patient with the same disease-causing gene was identified2 in 2018.

The disease was coined Takenouchi-Kosaki syndrome, after the two researchers who identified the mutation and its effects on human health.

Mutations in the genes FL11 and RUNX1 are known to cause a similar disease combination. But investigations in the patient who was tested in 2015 at the Center for Medical Genetics, Keio University School of Medicine, found that her condition was caused by a mutation in the gene CDC42, which was not inherited from the parents.

CDC42 had been studied extensively without being known as a disease-causing gene,” says pediatrician and clinical geneticist Kenjiro Kosaki, who led the investigations. “At least 5,000 studies about the gene were published prior to our discovery. All of a sudden, those 5,000 studies are medically relevant.”

Traditionally, researchers go through much effort to ‘knock out’ various genes in mice to understand their roles. “We now don’t need to turn to animal models because the patients are right there, waiting for new therapies,” Kosaki explains.

The patient’s condition somewhat resembled that of laboratory mice with knocked out CDC42 gene.

CDC42 encodes a protein that has a variety of roles. The mutation of the gene in humans could lead to developmental delay by affecting the protein’s role in nerve cell development. It could also have an impact on platelet formation by affecting the protein’s role in developing the internal cellular support structure needed for this process.

The findings represent “yet another mechanism leading to the combinatory phenotype of persistent macrothrombocytopenia and developmental delay,” the researchers concluded in their study published in the American Journal of Medical Genetics.

The program-affiliated researchers contributing to this research are from the Center for Medical Genetics, Keio University School of Medicine, Japan.


  1. Takenouchi, T., Kosaki, R., Niizuma, T., Hata, K. & Kosaki, K. Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: yet another locus for thrombocytopenia and developmental delay. American Journal of Medical Genetics 167, 2822–2825 (2015). | Article
  2. Motokawa, M., Watanabe, S., Nakatomi, A., Kondoh, T., Matsumoto, T., et al. A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome. Journal of Human Genetics 63, 387–390 (2018). | Article

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