A new pathogenic mechanism – sciencedaily

The family of genes known as the IKAROS Zinc Finger Protein (IKZF) is associated with the development of lymphocytes, a type of white blood cell involved in the immune response, which means that mutations in this family may be involved in immune system deficiencies. So far, most research has focused on the IKAROS protein, encoded by the IKZF1 gene, although the underlying mechanism by which IKAROS mutations cause the deficiencies is not yet fully understood. A mutation in AIOLOS – another member of the IKZF family which is encoded by the IKZF3 gene – has also been shown to cause hereditary immune deficiency. In addition to not functioning properly on its own, the resulting mutant protein interferes with the functioning of the IKAROS protein.

TMDU researchers discovered this new mechanism by investigating the cause of previously undescribed hereditary B cell deficiency observed in a family of patients. After sequencing all the genes encoding the proteins, the team focused their research on AIOLOS, as IKAROS is known to be the cause of the B cell deficiency. They showed that the mutant form of AIOLOS that was present in this family did not simply fail to function, but actively linked itself to a different DNA sequence than the normal version of the protein.

They then used a mouse model that harbors an equivalent AIOLOS mutation identified in patients to describe the underlying pathogenic mechanism. AIOLOS and IKAROS join together to form a “heterodimer”. The mutant form of AIOLOS retained the ability to bind to IKAROS but subsequently interfered with normal IKAROS function and led to recruitment of the heterodimer in the incorrect regions of the genome.

“This is a new pathogenic mechanism that we called heterodimeric interference,” explains lead author Motoi Yamashita, “where a mutant protein in a heterodimer hijacks the function of the normal partner protein.”

The team was then able to save part of the immune function in the mouse model by removing the dimerization domain of the AIOLOS mutant.

“The fact that we can save the phenotype in our mouse model indicates a potential therapeutic approach,” says Tomohiro Morio, lead author. “Deletion of the domain responsible for binding to IKAROS in the mutant AIOLOS protein could improve the immunodeficiency observed in patients.”

The discovery of this new pathogenic mechanism, heterodimeric interference, may well help shed light on many other disease processes such as autoimmunity and cancer development where mutant proteins act in the same way.

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Materials provided by Tokyo Medical and Dental University. Note: Content can be changed for style and length.