Primary immunodeficiencies, such as severe combined immunodeficiency disease (SCID), occur when the immune system does not function properly, leading to increased sensitivity to various infections, autoimmunity, and cancers. Most of these are inherited and have underlying genetic causes. A TMDU team has identified a new disorder resulting from a mutation in a protein called AIOLOS, which works through a previously unknown pathogenic mechanism called heterodimeric interference.
He gene family known as IKAROS zinc finger proteins (IKZFs) is associated with the development of lymphocytes, a type of white blood cell involved in the immune responseIt means that mutations may be involved in this family immune system deficiencies. To date, most research has focused on the IKAROS protein, encoded by the IKZF1 gene, although it is the basis mechanism whereby the IKAROS mutations cause the deficiencies is not yet fully understood. It has also been shown that a mutation in AIOLOS — another member of the IKZF family that is encoded by the IKZF3 gene — causes an inherited 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 while investigating the cause of a hereditary B-cell deficiency previously described 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 B cell deficiency. They showed that the mutant form of AIOLOS that there was in this family not only did it not work, but it was actively linked to a DNA sequence different from the normal version of the protein.
They continued to use a mouse model harboring an equivalent AIOLOS mutation identified in patients to outline the underlying pathogenic mechanism. AIOLOS and IKAROS join to form a “heterodimer”. The mutant form of AIOLOS retained the ability to bind IKAROS, but interfered with the normal function of IKAROS and caused the heterodimer to be recruited to the incorrect regions of the genome.
“This is a new pathogenic mechanism we call heterodimeric interference,” says lead author Motoi Yamashita, “where a mutant protein in a heterodimer hijacks the function of the normal partner protein.”
The team was able to rescue part of the immune function of the mouse model by eliminating the dimerization domain of the AIOLOS mutant.
“Being able to rescue the phenotype in our mouse model indicates a potential therapeutic approach, “says Tomohiro Morio, lead author.” Suppression of the domain responsible for binding IKAROS in the AIOLOS mutant protein could improve the immunodeficiency observed in patients “.
The discovery of this new pathogenic mechanism, heterodimeric interference, may help shed light on many other disease processes such as autoimmunity and the development of cancer, where mutant proteins act in the same way.
Motoi Yamashita et al, a variant in human AIOLOS impaired adaptive immunity by interfering with IKAROS, Immunology of nature (2021). DOI: 10.1038 / s41590-021-00951-z
Provided by Tokyo Medical and Dental University
Citation: When Crazy AIOLOS Drags IKAROS Down: A New Pathogenic Mechanism (2021, July 16) Retrieved July 17, 2021 at https://medicalxpress.com/news/2021-07-mad-aiolos-ikaros-pathogenic- mechanism.html
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