CPI Researchers identify the cause and mechanism of previously unexplained genetic condition

Friday, October 19, 2018

Image: Protein structure of IKK2 with substituted amino acid (red) shown within the activating pocket in the kinase domain.

Researchers at the Centre for Personalised Immunology have discovered the genetic cause and mechanism of a disease resulting in recurrent infections and inflammation. The research was led by Matthew Cook from the Centre for Personalised Immunology and Hirokazu Kanegane from Tokyo Medical and Dental University. Researchers identified two unrelated patients carrying an identical mutation in a gene called IKBKB.

The symptoms affecting these patients are a combination of the immune system being too weak and not mounting a proper response, while in other respects producing an excessive response.

“It is a disease which is characterised by immune deficiency where patients get recurrent infections, especially chest infections, including recurrent pneumonia, but paradoxically patients also suffer inflammatory diseases of the skin, lymph nodes and the spleen,” said Professor Cook.

The first patient with this mutation was identified through research done at the Centre for Personalised Immunology in Australia. A second patient with the same mutation was identified by the Japanese Researchers.

Chelisa Cardinez, PhD candidate at the ANU co-author of the publication, was awarded the Alan Harvey Scholarship in May of 2018. The Alan Harvey Scholarship supports students researching the human immune system and related diseases. Cardinez highlighted the importance of the collaboration between the Centre for Personalised Immunology and the Tokyo Medical and Dental University.

“Finding two patients with the same mutation, and then developing a mouse model to demonstrate causation, strengthens the case for establishing a mechanism of the disease.” said Cardinez.

CPI researchers investigate genes in order to find insights into the mechanisms of rare diseases. A main challenge of this research is to understand how genetic changes cause disease. CRISPR/cas9 gene editing is a useful tool for creating the same mutation seen in patient’s in animal models. 

“We used a CRISPR mouse model, which was carrying the same mutation observed in the patients, in order to identify causation between the mutation in the gene and the condition” Cardinez explained.

These animals showed an increase in IKK2 and NF-kB cell signalling and developed similar defects in their T and B cells, as observed in the human patients identified with the same mutation. The animal model confirms the mutation in the IKBKB gene is responsible for the patients’ symptoms.

Patients who have previously had this condition have been unwell for decades without a diagnosis. This research will now provide people with a definite diagnosis.

“In future, this strategy should prove important for investigating therapeutic interventions for personalised therapy.” Said Professor Cook.

The research has been published today in The Journal of Experimental Medicine. You can read more about the research here.

Credit: Cardinez et al., 2018